Use of Selective Chloride Channel Modulators to Treat Alcohol and/or Stimulant Substance Abuse

ABSTRACT

The invention relates to methods of and treatments for using pharmaceutical compositions from a class of compounds that directly or indirectly selectively modulates GABA A  chloride channel activity to treat alcohol and/or stimulant substance abuse. The present invention also relates to methods of, and protocols for, relieving symptoms associated with alcohol and/or stimulant substance abuse in a comprehensive treatment plan. More specifically, the present invention relates to the use of a selective chloride channel modulator, such as flumazenil, to treat alcohol and/or psychostimulant dependency, the withdrawal symptoms associated therewith, and the cravings associated therewith.

CROSS REFERENCE

The present invention is a continuation in part of U.S. patentapplication Ser. No. 10/621,229, entitled “Use of flumazenil in theproduction of a drug for the treatment of alcohol dependency”, filed onJul. 15, 2003.

FIELD OF THE INVENTION

The invention relates to methods of, and methodologies for, usingpharmaceutical compositions from a class of compounds that directly orindirectly selectively modulates GABA_(A) chloride channel activity totreat alcohol and/or psychostimulant substance abuse, including, but notlimited to, the various physical and psychological states that manifestan individual's impaired control over substance use, addiction,continued substance use despite harm, compulsive substance use,cravings, psychological dependence, physical dependence, tolerance, amaladaptive pattern of substance use, preoccupation with substance use,and/or the prevalence of withdrawal symptoms upon cessation of use. Thepresent invention also relates to methods of, and systems for, relievingsymptoms associated with said alcohol and stimulant substance abuse in acomprehensive treatment plan. More specifically, the present inventionrelates to the use of a compound, such as flumazenil, to treat alcoholand/or psychostimulant substance abuse, the withdrawal symptomsassociated therewith, and the cravings associated therewith.

BACKGROUND OF THE INVENTION

Alcohol and stimulant substance abuse disorders have a devastatingeconomic and societal impact on the United States population. Alcoholand stimulant substance dependency is a multi-factorial neurologicaldisease. The use of such drugs impacts an array of neurotransmissioncircuits in the brain, with a suggested final common pathway ofactivation of the mesolimbic reward circuit that is mediated viaenhanced dopamine release. Over time, repeated exposure to these drugscauses modification of the neurotransmission circuits and adaptations inpost-receptor signaling cascades. The effects of this neuronalmodification are twofold. First, a reduction in the ability of naturalrewards to activate the reward pathways leads to depressed motivationand mood, and increased compulsion to take more drugs. Second, there isa production of long-lasting memories related to the drug experiencethat, when stimulated by stressful events or exposure to drug-associatedor mood-associated cues, act to stimulate cravings for the drug.

For many individuals, an innate neurochemical anomaly renders themsusceptible to substance dependency or addictive behavior, even beforeany long-term effects of alcohol on neurological processing are evident.It is clear, however, that excessive drinking over time can lead to theimpairment of brain function and result in structural brain changes infrontal and prefrontal areas of the brain, which are associated withcognition. Impaired cognition and judgment can therefore becomepermanent.

Alcohol affects the mesolimbic dopamine circuit by modifying theactivity of two key receptors in the dopamine circuit, the GABA_(A)receptor and NMDA receptor. GABA (gamma-aminobutryic acid) is aneurotransmitter that is a predominant inhibitory transmitter in areasof the brain such as the cortex and basal ganglia. The NMDA(N-methyl-D-aspartate) receptor is a ligand-gated ionic channelactivated by and involved in the release of the neurotransmitterglutamate, which is an important excitatory transmitter in the brain.The positive affect on the mesolimbic dopamine circuit creates aself-reinforcing cycle of neuropathophysiological reward that drivesindividuals to become alcohol dependent. Alcohol increases chloridechannel ion flow, relative to the post-synaptic chloride channel atrest, by engaging a GABA_(A) receptor site. Benzodiazepines have asimilar affect.

Acute exposure to alcohol results in the up regulation of NMDA and downregulation of the GABA-ergic system. Repeated exposure results incross-tolerance and cross-dependence between alcohol andbenzodiazepines. Consequently, an alcohol dependent person experiencesstress, a down regulation of GABA_(A) and an increase in the severity ofwithdrawal symptoms when he or she attempts to withdraw.

Therefore, when an alcoholic attempts to initiate abstinence or stopconsuming alcohol, he or she may experience withdrawal symptoms,including cravings, which often result in a failure to stop consumingalcohol. Traditional alcohol withdrawal symptoms include anxiety,tremors, difficulty sleeping, elevated pulse and blood pressure, nausea,and vomiting. In some cases, withdrawal symptoms may be more severe andresult in complications, including seizures, hallucinosis,hallucinations with severe tremors (or “delirium tremens”, DTs) anddifficulty regulating body temperature. These complications may often befatal. In an exemplary case, withdrawal symptoms begin appearing 6 to 12hours after a prior consumption of alcohol. Alcohol withdrawal syndromemay occur 6 to 48 hours after a prior consumption of alcohol.

Psychostimulants are a class of central nervous system stimulants andinclude cocaine, crack cocaine, ephedrine, amphetamines, such asdextroamphetamine (commonly referred to as amphetamine),methamphetamine, and phenmetrazine, methylenodioxyamphetamine (MDA), andmethylenodioxymethamphetamine (MDMA or “ecstasy”), and analogs thereof.Amphetamine-like drugs are classified as indirect action agonists ofnoradrenergic, dopaminergic, and serotonergic synapses which result frominhibiting both neurotransmitters reuptake and the enzyme monoamineoxidase (MAO). They are competitive inhibitors of noradrenaline anddopamine transport and, in high doses, also inhibit serotonin reuptake.They cause non-calcium dependent dopamine and noradrenaline release.

Stimulants affect a number of neurological circuits, includingdopaminergic, beta-adrenergic, serotonergic, glutamatergic, GABAergiccircuits, and ultimately results in impaired dopamine function. GABA_(A)functionality is eventually impaired.

At lower doses, stimulants result in a feeling of euphoria, an increasein energy, a decrease in fatigue, and an increase in mental acuity. Asdosing increases, a person starts to experience tremors, emotionalinstability, restlessness, irritability, and feelings of paranoia andpanic. At higher doses, a person experiences intense anxiety, paranoia,hallucinations, hypertension, tachycardia, hyperthermia, respiratorydepression, heart failure, and seizures.

Traditional withdrawal symptoms for those trying to end their abuse ofpsychostimulants include: depressed mood, fatigue, vivid and unpleasantdreams, difficulty sleeping or excessive sleeping, increased appetite,anxiety, and agitation. Cravings for the psychostimulant areparticularly pronounced and may recur for many months, if not years. Areturn of “normal” mood and the ability to experience pleasure may takea significant amount of time due to the depletion or modification ofneurotransmitters.

Alcohol and psychostimulant substance abuse are often associated withchanges in food selection and intake that lead to calorie and proteinmalnutrition and disruption of energy expenditure. The resultingmalnutrition is related to deficient food intake, malabsorption,increased protein turnover, liver disease, intensity of drug addiction,anorexia, and poor food and drink consumption. Furthermore, thedisturbance of social and familial links can itself result in poornutrition. Malnutrition, in turn, is associated with impairment ofimmune function. Therefore, restoration and maintenance of normalphysiological function can be regarded as an important objective whentreating substance dependencies. Effective treatment of alcoholsubstance abuse should address the neurological, nutritional, andpsychosocial disturbances that both cause and exacerbate the abuse.

The customary treatment of alcohol dependency includes theadministration of vitamin B and C complexes, benzodiazepines (to calmagitation and blunt withdrawal symptoms), and, sometimes, disulfuram (toprevent alcohol use). The traditional medical detoxifications involvereplacing alcohol with substances pharmacologically similar to alcoholin order to reduce withdrawal agitation. Detoxification can take 3-5days, involves sedation with potentially dependence forming drugs, andis generally uncomfortable for the patient.

Traditional treatments for managing withdrawal and craving for alcoholand/or psychostimulants (such as cocaine) may include the administrationof benzodiazepines (e.g. lorezepam) if agitation or anxiety is present,antidepressants to treat persistent depression and dopamine-agonists toincrease brain dopamine. These treatments, however, have limited successand have high dropout rates. Dropout can refer to several differenttypes of treatment events related to the premature cessation oftreatment, including times when patients dropout during treatment andwhen patients relapse following treatment.

A review of the various pharmacological treatments existing for thetreatment of alcohol dependency can be found in A Practice Guideline forthe Treatment of Patients With Substance Use Disorders Alcohol, Cocaineand Opioids, produced by the Work Group on Substance Use Disorders ofthe American Psychiatric Association and published in Am. J. Psychiatry152:11, November 1995 Supplement. An updated review of the treatment ofalcohol dependency was created by Mayo-Smith et al., JAMA Jul. 9, 1997,Vol. 278, No. 2, who conclude by indicating that the benzodiazepines(alprazolam, diazepam, halazepam, lorazepam or oxazepam) are agentssuitable for the treatment of alcohol dependency, whereas beta-blockers(propranolol), neuroleptics (chlorpromazine and promazine), clonidineand carbamazepine, may be used in coadjuvant therapy, but their use isnot recommended as a monotherapy. A benzodiazepine is any of a group ofchemically similar psychotropic drugs with potent hypnotic and sedativeaction, used predominantly as anti-anxiety (anxiolytic) andsleep-inducing drugs. Side effects of these drugs may include impairmentof psychomotor performance; amnesia; euphoria; dependence; and rebound(i.e., the return of symptoms) transiently worse than before treatment,upon discontinuation of the drug.

In certain conventional uses, flumazenil, an imidazobenzodiazepinederivative, antagonizes the actions of benzodiazepines on the centralnervous system. In conventional doses, flumazenil [ethyl8-fluoro-5,6-dihydro-5-methyl-6-oxo-4H-imidazol[1,5-a][1,4]benzodiazepine-3-carboxylate]therefore acts as a benzodiazepine antagonist which selectively blocksthe effects exerted on the central nervous system via the benzodiazepinereceptors. This active principle is indicated to neutralize the centralsedative effect of the benzodiazepines; consequently, it isconventionally used in anesthesia to end the general anesthesia inducedand maintained with benzodiazepines in hospitalized patients, or to stopthe sedation produced with benzodiazepines in patients undergoing briefdiagnostic or therapeutic procedures on an inpatient or outpatientbasis.

Some clinical studies have examined the role of flumazenil in thereversal of alcohol withdrawal syndrome. Gerra et al., 1991, CurrentTherapeutic Research, Vol. 50, 1, pp 62-66, describe the administrationto 11 selected alcoholics (who did not have cirrhosis, metabolicdisorders, convulsions, addictions to other substances or psychiatricdisorders) of 2 mg/day of flumazenil divided into 4 doses (0.5 mg),intravenously (IV) via a continuous drip, in saline solution, every 6hours for 48 hours. The use of 0.5 mg of flumazenil is based on thepresentation of pharmaceutical preparations that contain said activeprinciple but not on studies performed in humans concerning the level ofoccupation of the receptors involved. The flumazenil was administered atthe rate of 0.5 mg of flumazenil every 6 hours (i.e., 0.08 mg/hour offlumazenil). The tests performed by Gerra et al. present somecharacteristics that are far from the actual circumstances, for example,the tests were performed on a small sample (11 individuals) of selectpatients not representative of the pathology considered since it isrelatively customary that these patients may have cirrhosis, metabolicdisorders, addictions to other substances (cocaine, heroin, etc.) and/orpsychiatric disorders. Moreover, Gerra et al. do not present dataconcerning the evaluation of dependency or craving either before orafter administration of the drug. Most importantly, however, Gerra etal. discloses the administration of very small quantities of flumazenilover long periods of time, which was not particularly effective attreating alcohol dependency. Nutt et al. [Alcohol & Alcoholism, 1993,Suppl. 2, pp 337-341. Pergamon Press Ltd.; Neuropschychopharmacology,1994, Vol. 10, 35, part 1, Suppl., p. 85f) describe the administrationto 8 alcoholics in the acute withdrawal phase of 2 mg of flumazenil, byIV, for 1 minute. The results obtained after the administration offlumazenil were not completely satisfactory since in some cases, therewas an immediate worsening of the withdrawal symptoms, especially ofsweats and anxiety. In other cases, the withdrawal symptoms disappearedbut returned a few hours later. Since flumazenil is metabolized andeliminated very rapidly, the IV administration of a relatively high doseof flumazenil in a single dose of 2 mg, for 1 minute, has severaldisadvantages since such dosing triggers undesired side effects, and thebulk of flumazenil administered yields no pharmacological response andresults in unnecessary expense.

Moreover, the results obtained by Gerra et al. and by Nutt et al. arenot conclusive since in some cases, no significant changes were observedin either the blood pressure or the heart rate of patients after theadministration of flumazenil, an immediate worsening of the withdrawalsymptoms was observed, especially sweats and anxiety, and the tests wereperformed using a very small non-representative patient sample.

In two articles by Sheryl S. Moy (Skipper Bowles Center for AlcoholStudies, Department of Psychiatry and UNC Neuroscience Center),investigators disclose the use of flumazenil to block anxiety created byethanol withdrawal in rats. According to Moy et al. (2000), in ratmodels of the ethanol withdrawal syndrome, flumazenil can reverseanxiogenic withdrawal effects such as inhibition during a socialinteraction test (File et al. 1989, 1992) and reduced open armexploration on an elevated plus maze (Moy et al. 1997). Further in Moyet al. (2000) and Uzbay et al. (1995) it was reported that flumazenilcould prevent the agitation and stereotyped behavior induced bywithdrawal from long-term ethanol exposure in rats. Doses, however, wereprovided for rat models and cannot be readily translated to human dosagelevels. Moreover, the prior art teaches the use of flumazenil in aconventional benzodiazepine treatment model, which requires thesubstitution of ethanol usage with large quantities of benzodiazepine toalleviate withdrawal symptoms.

However, all disclosed uses of flumazenil in the treatment of alcoholwithdrawal and addiction have relied on either the single administrationof large quantities of flumazenil or on-going administrations of verylow quantities of flumazenil over long periods of time. Moreover, thedisclosed administrative regimens has not applied the use of flumazenil,or a class of compounds represented by flumazenil, for treatingpsychostimulant substance abuse at all. Furthermore, conventionaltreatments for alcohol and/or psychostimulant dependency have hadlimited success and often have undesirable side effects. New approachesare needed that can improve treatment outcomes and reduce the risk ofrelapse. Thus, an improved treatment methodology for treating alcoholand/or psychostimulant substance abuse is desirable.

In addition, conventional treatments for controlling withdrawal symptomsand cravings for alcohol and/or psychostimulants have had limitedsuccess and often have undesirable side effects. Thus, an improvedtreatment methodology for controlling cravings and withdrawal symptomscaused by alcohol and/or psychostimulant substance abuse would bedesirable.

It would also be desirable to have an improved methodology and protocolfor treating alcohol and/or psychostimulant substance abuse, whichresults in reduced patient dropout rates.

SUMMARY OF THE INVENTION

The present invention is directed towards various methods and protocolsfor the treatment of alcohol and/or psychostimulant substance abusebased on safe and effective administration of a class of compounds thatdirectly or indirectly selectively modulates GABA_(A) chloride channelactivity, such as, but not limited to flumazenil, and which requires ashort period of time to effectively eradicate symptoms of alcohol and/orpsychostimulant substance abuse. As defined herein, the class ofcompounds that selectively modulates GABA_(A) chloride channel activity(referred to herein as Selective Chloride Channel Modulators) isintended to cover the selective modulation of chloride channel activityand does not encompass full agonists of the GABA_(A) receptor, such asfluoxetine benzodiazpenes. Additionally, as defined herein, the termsubstance abuse is used to refer to the various physical andpsychological states that manifest an individual's impaired control overalcohol and/or stimulant substance use, continued alcohol and/orstimulant substance use despite harm, addiction, compulsive alcoholand/or stimulant substance use, cravings, psychological dependence,physical dependence, tolerance, a maladaptive pattern of alcohol and/orstimulant substance use, preoccupation with alcohol and/or stimulantsubstance use, and/or the prevalence of withdrawal symptoms uponcessation of use.

It is another object of the present invention to provide for methods andprotocols for the treatment of alcohol and/or psychostimulant substanceabuse that includes administration, to a patient in need of saidtreatment, of a therapeutically effective quantity of a compound thatdirectly or indirectly selectively modulates chloride channel activity,administered in multiple doses at a predetermined rate, until saidtherapeutically effective quantity to treat alcohol and/orpsychostimulant substance abuse has been reached.

It is another object of the present invention to provide for methods andprotocols that reduce cravings and withdrawal symptoms from addiction toalcohol and/or psychostimulants that includes administration, to apatient in need of said treatment, of a therapeutically effectivequantity of a compound that directly or indirectly selectively modulateschloride channel activity, administered in multiple doses at apredetermined rate, until said therapeutically effective quantityadministration reduces cravings and withdrawal symptoms from addictionto alcohol and/or psychostimulants.

It is another object of the present invention to provide a methodologyfor controlling cravings, reducing withdrawal symptoms and treatingaddiction to alcohol and/or psychostimulants. It is yet another objectof the present invention to administer a compound that directly orindirectly selectively modulates chloride channel activity, such as, butnot limited to flumazenil, in a therapeutically effective quantity so asto control cravings and withdrawal symptoms. In addition, themethodology according to the invention also results in improvedcognitive function.

It is yet another object of the present invention to provide amethodology and protocol for reducing patient dropout rates for thosepatients undergoing treatment for alcohol and/or psychostimulantaddiction. The invention includes the administration of a compound thatdirectly or indirectly selectively modulates chloride channel activityin a therapeutically effective quantity resulting in higher patientrecovery rates compared to conventional treatments. This, in turn,results in lower patient dropout rates.

Optionally, it is another object of the present invention to provide foradministration of therapeutically effective amounts of flumazenil inmultiple doses at a predetermined rate which results in significantlylower patient dropout rates and fewer side effects in the patient.

BRIEF DESCRIPTION OF THE DRAWINGS

These and other features and advantages of the present invention will beappreciated, as they become better understood by reference to thefollowing Detailed Description when considered in connection with theaccompanying drawings, wherein:

FIG. 1 is a flowchart depicting various pre-treatment, co-treatment, andpost-treatment phases of an exemplary methodology for usingpharmaceutical compositions from a class of compounds that directly orindirectly selectively modulate GABA_(A) chloride channel activity totreat alcohol and/or psychostimulant substance abuse;

FIG. 2 is a flowchart illustrating a first embodiment of an exemplarymethodology to treat alcohol substance abuse;

FIG. 3 is a flowchart illustrating a second embodiment of an exemplarymethodology to treat alcohol substance abuse;

FIG. 4 is a flowchart illustrating a third embodiment of an exemplarymethodology to treat alcohol substance abuse;

FIG. 5 is a flowchart illustrating a first embodiment of an exemplarymethodology to treat stimulant substance abuse; and

FIG. 6 is a flowchart illustrating a second embodiment of an exemplarymethodology to treat stimulant substance abuse.

DETAILED DESCRIPTION OF THE INVENTION

The present invention is directed towards methods and protocols for thetreatment of alcohol and/or psychostimulant substance abuse based onsafe and effective administration of a class of compounds that directlyor indirectly selectively modulates chloride channel activity, such as,but not limited to flumazenil, and which requires a short period of timeto effectively eradicate symptoms of alcohol and/or psychostimulantsubstance abuse.

The present invention provides for a comprehensive treatment approachfor managing the recovery process for alcohol and/or stimulant substanceabuse. The methodology of the present invention is also designed toreduce inpatient treatment time (2-3 days), improve treatment completionrates, reduce cravings, and decrease patient relapse rates versuscurrent alcohol and/or stimulant abuse treatment options.

As used in this description, the term substance abuse is used to referto the various physical and psychological states that manifest anindividual's impaired control over alcohol and/or stimulant substanceuse, continued alcohol and/or stimulant substance use despite harm,compulsive alcohol and/or stimulant substance use, and/or cravings. Theterm is intended to include psychological dependence, physicaldependence, tolerance, a maladaptive pattern of alcohol and/or stimulantsubstance use, preoccupation with alcohol and/or stimulant substanceuse, and/or the prevalence of withdrawal symptoms upon cessation of use.

As used in this description, the term drug is used to refer toprescription or non-prescription pharmaceutical compositions and/ormedications that include an active ingredient and, optionally,non-active, buffering, or stabilizing ingredients, includingpharmaceutically acceptable carriers or excipients suitable for the formof administration of said pharmaceutical compositions.

In particular, the term drug is used to refer to a class of compoundsthat directly or indirectly selectively modulates chloride channelactivity (“Selective Chloride Channel Modulators”), e.g. chloride ionflow across the channel, with respect to GABA_(A) receptors in thebrain. One of ordinary skill in the art would appreciate that, asdefined herein, the term Selective Chloride Channel Modulators isintended to cover the selective modulation of chloride channel activityand does not encompass full agonists of the GABA_(A) receptor, such asbenzodiazpenes.

In one embodiment, the Selective Chloride Channel Modulators comprises apartial allosteric modulator that acts with high affinity but lowpotency at GABA_(A) receptor sites. The partial allosteric modulators ofthe present invention are capable of engaging a GABA_(A) receptor sitebased upon a conformational compatibility with the GABA_(A) receptorsite. In one embodiment, the partial allosteric modulators of thepresent invention are capable of displacing, modifying, or otherwiselimiting the affects of endogenous benzodiazepine inverse agonists bypreventing their engagement with a GABA_(A) receptor site. In anotherembodiment, the partial allosteric modulators of the present inventionhave a mild inverse agonist affect on the GABA_(A) receptor due to ahigh affinity and low potency.

In another embodiment, the Selective Chloride Channel Modulatorscomprises a partial allosteric modulator that acts to reset GABA_(A)receptivity and thereby increase receptivity and chloride channel ionflow without requiring alcohol.

In another embodiment, the Selective Chloride Channel Modulatorscomprise a composition that functions as a partial agonist of theGABA_(A) receptor by displacing, modifying or otherwise limiting theaffects of endogenous benzodiazepine inverse agonists, such as diazepambinding inhibitor (DBI), and that functions as an inverse agonist of theGABA_(A) receptor if not in the presence of an endogenous benzodiazepineinverse agonist.

In another embodiment, Selective Chloride Channel Modulators comprise acomposition that functions as a partial agonist of the GABA_(A) receptorby displacing, modifying or otherwise limiting the affects ofbenzodiazepine inverse agonists, such as diazepam binding inhibitor(DBI), and that has substantially no affect on the GABA_(A) receptor inthe absence of a benzodiazepine inverse agonist.

In another embodiment, Selective Chloride Channel Modulators comprisecertain imidazobenzodiazepines and derivatives of ethyl8-fluoro-5,6-dihydro-5-methyl-6-oxo-4H-imidazo-[1,5-a][1,4]benzodiazepine-3-carboxylate, including various substitutions of in thecarboxylate functional group, such as carboxylic acids, esters, acylchlorides, acid anhydrides, amides, nitrites, alkyls, alkanes,cycloalkanes, alkenes, alcohols, aldehydes, ketones, benzenes, phenyls,and salts thereof. In another embodiment, Selective Chloride ChannelModulators comprise flumazenil and carboxylic acids, esters, acylchlorides, acid anhydrides, amides, nitrites, alkyls, alkanes,cycloalkanes, alkenes, alcohols, aldehydes, ketones, benzenes, phenyls,and salts thereof.

As used in this description, the term patient refers to a male or femalehuman being of any race, national origin, age, physiological make-up,genetic make-up, disease predisposition, height, or weight, and havingany disease state, symptom or illness.

It should be appreciated that the administration of a Selective ChlorideChannel Modulator may be achieved through any appropriate route ofadministration, for example, orally, inhaled, rectally, sublingually,bucally, transdermally, nasally, or parenterally, for which it will beformulated using the appropriate excipients for the form ofadministration. In one embodiment, the Selective Chloride ChannelModulator is administered intravenously (IV). In another embodiment, theSelective Chloride Channel Modulator is administered using an infusionpump. In another embodiment, the Selective Chloride Channel Modulator isadministered using a syringe pump that provides the continuous, orphysician-controlled, delivery of the drug. In another embodiment, theSelective Chloride Channel Modulator is administered from pre-filledsyringes that automatically deliver a predetermined dose over aninfusion period.

It should further be appreciated that the methods and processes of thepresent invention can be implemented in a computer system having a datarepository to receive and store patient data, a memory to store theprotocol steps that comprise the methods and processes of the presentinvention, a processor to evaluate patient data in relation to saidprotocol steps, a network interface to communicate via a network withother computing devices and a display to deliver information to users.In one embodiment, specific protocol steps are stored in said memory andcompared against patient data to determine which protocol steps shouldbe applied in accordance with the patient data. Results of thecomparison are communicated to a user via a network and other computingdevices or display. The methodologies of the present invention aretherefore accessed, tailored, and communicated as a software programoperating on any hardware platform.

Reference will now be made in detail to specific embodiments of theinvention. While the invention will be described in conjunction withspecific embodiments, it is not intended to limit the invention to oneembodiment.

1. Introduction to an Exemplary Methodology

Referring to FIG. 1, the treatment methodology of the present invention100 is a system consisting of multiple components administered on apre-admittance, inpatient, outpatient, and post-discharge basis for thetreatment of alcohol dependence. The methodology is designed to reducecravings associated with and following alcohol withdrawal, and to helpthe dependent patient maintain abstinence and reduce harmful behaviorduring outpatient and follow-up care. The methodology will largely bedescribed with reference to the alcohol dependence methodology in thissection, but is not limited to such methodology. A separate methodologymay be administered for psychostimulant, or combined alcohol andpsychostimulant, dependence. Additionally, separate methodologies may becatered to outpatient vs. inpatient treatment settings.

As shown in FIG. 1, the treatment methodology 100 for alcohol dependencehas multiple phases and components that, in combination, provide acomprehensive and integrated neurological, physiological, andpsychosocial approach for the alcohol-dependent patient. Each componenthas been selected to address specific effects of chronic alcoholconsumption and the corresponding symptoms of alcohol withdrawal, withthe objective of restoring a balance in neurological circuits. Themethodology does not address the specific physical injury, such as liverdamage, that is often associated with alcohol dependence. It is,therefore, essential that each patient be assessed and the appropriatetreatments be instituted to address physical injury, with dueconsideration for the potential interaction of any drugs used for thistreatment with those used for the dependency treatment.

While the present methodology can be applied to any patient, it ispreferred that the patient be equal to or greater than eighteen yearsold. It is also preferred that the patient meet at least a portion ofthe DSM IV criteria for substance dependence on stimulants or alcohol.The DSM IV criteria is known to those of ordinary skill in the art andcan be described as a maladaptive pattern of alcohol and/or stimulantsubstance use, leading to clinically significant impairment or distress,as manifested by any of the following, occurring at any time in the same12-month period:

-   -   (1) Tolerance, as defined by either of the following:        -   a. A need for markedly increased amounts of the substance to            achieve intoxication or desired effect.        -   b. Markedly diminished effect with continued use of the same            amount of the substance.    -   (2) Withdrawal, as manifested by either of the following:        -   a. The characteristic withdrawal syndrome for the substance.        -   b. The same (or a closely related) substance is taken to            relieve or avoid withdrawal symptoms.    -   (3) The substance is often taken in larger amounts or over a        longer period than was intended (loss of control).    -   (4) There is a persistent desire or unsuccessful efforts to cut        down or control substance use (loss of control).    -   (5) A great deal of time is spent in activities necessary to        obtain the substance, use the substance, or recover from its        effects (preoccupation).    -   (6) Important social, occupational, or recreational activities        are given up or reduced because of substance use (continuation        despite adverse consequences).    -   (7) The substance use is continued despite knowledge of having a        persistent or recurrent physical or psychological problem that        is likely to have been caused or exacerbated by the substance        (adverse consequences).

It should further be noted that certain exclusion criteria should beapplied to the screening of patients. The exclusion criteria may betailored to an outpatient or inpatient treatment scenario. For example,it is preferred not to treat a patient on an inpatient basis for alcoholor stimulant dependence where the patient has current medical orpsychiatric problems that, per the screening physician, requireimmediate professional evaluation and treatment, has current medical orpsychiatric problems that, per the screening physician, render theclient unable to work successfully with the methodology or with thestaff administering the treatment, has current benzodiazepine and othersedative-hypnotic-anxiolytic use (urine toxicology must be negative) oris taking anti-psychotic medication(s).

Similarly, it is preferred not to treat a patient on an inpatient basisfor alcohol dependence where the patient has current medical orpsychiatric problems that, per the screening physician, requireimmediate professional evaluation and treatment, has current medical orpsychiatric problems that, per the screening physician, render theclient unable to work successfully with the methodology or is currentlytaking tricyclic anti-depressants or benzodiazepines.

Patients admitted for the methodology for alcohol (and/orpsychostimulant) dependence are initially treated with medications for 2days of neurostabilization (which may include detoxification) along withnutritional supplements to ensure their supply does not limit the body'sability to restore an appropriate metabolic balance (such asphysiological amino acid and protein turnover). Subsequent patientmanagement includes maintenance pharmacotherapy with protocolcomponents, combined with optional (but recommended) psychosocial and/orbehavioral therapies, which are described in detail below. The combinedeffects of pharmacotherapy and psychosocial support are designed tominimize withdrawal symptoms, help prevent relapse, and reduce cravingsfor the dependent substance. Ongoing psychosocial and/or behavioraltreatment is tailored to optimize the probability of long-term recovery.

2. Exemplary Methodology Components (100)

Referring back to FIG. 1, the exemplary treatment methodology 100 of thepresent invention comprises pre-treatment, co-treatment, andpost-treatment phases further comprising various components of anexemplary methodology for using pharmaceutical compositions from a classof compounds that directly or indirectly selectively modulate GABA_(A)chloride channel activity to treat addiction to alcohol and/orpsychostimulants. As described herein, reference will be made tospecific components of the individual phases of the treatmentmethodology 100. It should be noted, however, that the individualcomponents comprising each phase of the methodology—pre-treatment,co-treatment, and post-treatment—may be performed in different ordersand should be determined on a per-patient basis. Thus, any reference toadministering the individual components of the phases of methodology 100in a particular order is exemplary and it should be understood to one ofordinary skill in the art that the administration of methodology 100 mayvary depending on the assessed needs of the patient.

a. Pre-Treatment (110)

Referring back to FIG. 1, prior to admittance into the treatment programof the present invention, each patient should undergo a pre-treatmentanalysis 110. The pre-treatment analysis 110 may be used to determinewhether a patient is an optimal candidate for the treatment methodologyof the present invention. In addition, the pre-treatment process 110 maybe administered to prepare a patient for admittance into the treatmentmethodology 100 of the present invention. The pre-treatment phasetypically includes, but is not limited to a complete physicalexamination 110 a, a complete psychological examination 110 b, a CIWAAssessment 110 c, and a determination of required medications 110 d. Thecomponents of the pre-treatment phase of the methodology 100 of thepresent invention are described in greater detail below.

i. Complete Physical Examination (110 a)

Before starting the treatment, it is preferred that patient undergo acomplete medical examination. The patient is preferably monitored toobtain a complete blood count, a biochemical profile [for example,creatinine, glucose, blood urea nitrogen (BUN), cholesterol (HDL andLDL), triglycerides, alkaline phosphatase, LDH (lactic dehydrogenase)and total proteins], hepatic function tests [GOT, GPT, GGT, bilirubin),electrocardiogram and, if need be, pregnancy test and x-ray examination.Exclusion criteria is applied to ensure no other acute or uncompensatedillness exists within the patient and to ensure that the patient doesnot require, or is currently not taking, a drug that is contraindicatedwith flumazenil or another Selective Chloride Channel Modulator if beingused.

ii. Complete Psychological Examination (110 b)

Before starting the treatment, it is also preferred that patient undergoa complete psychological medical examination.

iii. Withdrawal Symptomatology (110 c)

Before and after the administration of the Selective Chloride ChannelModulator, the withdrawal symptomatology should be measured using theCIWA-A evaluation (Adinoff et al., Medical Toxicology 3:172-196 (1988)),as well as heart rate and blood pressure.

iv. Determination of Required Medications (110 d)

The physician in charge should make a determination, prior to treatment,if a patient diagnosed with any symptom or disorder, other than alcoholor psychostimulant addiction, should receive medication for thisdisorder. For example, a patient diagnosed with arterial hypertensionshould be prescribed with the appropriate medication or continue withany existing medication.

b. During Treatment (120)

Referring back to FIG. 1, if a patient is admitted into the treatmentprogram of the present invention, the patient will then begin the duringtreatment phase 120 of the treatment methodology 100 of the presentinvention. During treatment, a patient will preferably be administeredpharmaceutical compositions 120 a, adhere to a prescribed diet 120 b,maintain an exercise regimen 120 c, and attend inpatient therapysessions 120 d. The exemplary components of the during treatment phaseof the treatment methodology 100 are described in greater detail below,but are not limited to such options.

i. Pharmaceutical Compositions (120 a)

Various pharmaceutical compounds may be administered during treatmentwith a benzodiazepine antagonist as with the methodology of the presentinvention. These are listed below.

1. Selective Chloride Channel Modulator

In one embodiment, the Selective Chloride Channel Modulator flumazenilis used because it functions to effectively regulate GABA_(A) receptoractivity and minimize the severity of conventional withdrawal symptoms.The use of flumazenil may normalize shifts in neuronal GABA_(A) activityand subsequent dopamine malfunctions resulting from chronic exposure toethanol. Specifically, when used in accordance with the novel inventionpresented herein, flumazenil is anxiolytic, thereby ameliorating animportant withdrawal symptom, and decreases cravings.

2. Gabapentin

a. Use of Gabapentin

Gabapentin is an anxiolytic and anticonvulsant medication typicallyprescribed to patients suffering from epilepsy (effectively lowers brainglutamate concentrations) and has also been used in the treatment ofanxiety disorders such as social anxiety disorder andobsessive-compulsive disorder. Gabapentin compliments flumazenil inhelping normalize GABA and glutamate transmission, thus enhancing GABAtone.

Gabapentin was originally designed as a structural analog of GABA. Itlikely operates as a calcium N-channel blocker. Gabapentin also exhibitspost-synaptic effects modulating NMDA-mediated transmission by 1)reducing NMDA/Glutamatergic tone and 2) indirectly helping compensatefor reduced GABAergic tone due to upregulated NMDA activity in thewithdrawn state. Gabapentin provides for an improved quality andquantity of sleep and an improved anxiety state. As a result of itsabove-mentioned qualities, gabapentin decreases withdrawal symptoms.

b. Key Pharmacologic Safety Considerations for the Use of Gabapentin

Prior to administering gabapentin to a patient, it is essential toassess the patient for interactions and contraindications. Gabapentin isto be used in adjunctive therapy in the treatment of epilepsy seizures(partial) and for the management of postherpetic neuralgia. Gabapentinis not appreciably metabolized and is excreted unchanged with anelimination half-life of 5-7 hours. Possible side effects from the useof gabapentin are dizziness, somnolence, other symptoms/signs of CNSdepression, nausea, ataxia, tremor, and peripheral edema. In personswith epilepsy, abrupt discontinuation may increase seizure frequency. Noclinically significant drug interactions have been reported in theliterature.

3. Hydroxyzine HCl

Hydroxyzine, an H1 histamine receptor antagonist, is indicated fortreatment of generalized anxiety disorder and for use in the managementof withdrawal from substance dependence during both the initial phase ofinpatient treatment and post-discharge care (as necessary). It also hasanti-emetic and skeletal muscle relaxation benefits and can be used as asedative. This sedative effect can be useful for treating thesleep-disordered breathing and increased periodic leg movements thatcontribute to the insomnia often seen in patients recovering fromalcohol dependency. This helps address on-going insomnia that, for somepatients, is significantly associated with subsequent alcoholic relapse.

Hydroxyzine is rapidly absorbed and yields effects within 15-30 minutesafter oral administration. In addition, hydroxyzine aids the substancewithdrawal process through anxiolytic, anti-nausea, relaxant, andvarious other properties. It should be noted that the effects of othersedating or tranquilizing agents might be synergistically enhanced withthe administration of hydroxyzine. Exemplary drugs includepharmacological compositions having the trade names Atarax and Vistaril.

4. Vitamin B

a. Fortified Vitamin B Complex

Chronic alcohol consumption depletes the levels of several vitamins,particularly the B vitamins (also known as the stress vitamins). Thesevitamins are required by the body to convert food into energy, maintainthe integrity of tissues such as the skin and liver, and combat physicalor emotional stress. Administration of vitamin B complex as part of themanagement of the alcohol-dependent patient may help to ameliorate therisk of Wernicke-Korsakoff syndrome and alcoholism-induced cognitivedeficit. The present invention preferably includes the provision of anutritional supplement of fortified vitamin B-complex (thiamine—B1,riboflavin—B2, niacin—B3, pyridoxine—B6, folic acid—B9,cyanocobalamin—B12, pantothenic acid, and biotin) to patients dailyduring stabilization with the methodology and post-discharge for as longas medically beneficial.

b. IV Vitamin B Supplement

Alcohol abusers tend to have poor nutritional status, exacerbated bypoor diet, gastritis, duodenitis, frequent vomiting, physical illness,and weight loss. Thus, there is a need for parenteral vitamins. Thiamineabsorption from oral treatment tends to vary; alcohol in the gutinterferes with absorption. Thus, there is a potentially large thiaminedeficiency in alcohol dependence. Oral dosing is unlikely to meetmaintenance requirements. Thiamine decreases sodium transport in alcoholdependence. In addition, it is a catalyzer of key metabolic actions ofGABA.

5. Protein Supplement Drink

Chronic alcohol consumption increases the body's overall rate ofmetabolism, and alcohol-dependent subjects often have reduced skeletalmuscle synthesis and skeletal muscle mass. Alcohol reduces proteinsynthesis in a range of tissues, including but not limited to skeletalmuscle. This can lead to a net loss of protein from and impairedfunction in important organs and tissues such as the heart, liver andkidneys. To counteract these effects, a protein supplement drink ispreferably provided daily to the patient during inpatient stabilizationwith the methodology. In addition, the increased levels of serum aminoacids (such tyrosine and tryptophan) provide the substrate to helpre-establish alcohol- and withdrawal-induced alterations in levels ofneurotransmitters such as dopamine and serotonin.

6. Glutamine

Glutamine is the most abundant amino acid in the body and is anessential nutrient for actively replicating cells, such as those of theimmune system. Glutamine is also a precursor for both glutamate andGABA. In skeletal muscle glutamine is the most abundant amino acid andits depletion is associated with loss of muscle mass, a process that canbe reversed by glutamine supplementation.

Alcohol has direct effects on the innate immune system. Alcoholpredisposes dependent patients to infections and sepsis by blunting theinitial response to pathogens. Withdrawing alcohol does not immediatelyreverse this effect. Glutamine, given as a nutritional supplement, is animportant part of the methodology. Glutamine supplementation provides animmediate supply of fuel to the immune system, possibly enhancing immunefunction. Glutamine supplementation helps to restore the plasma andmuscle levels of glutamine, which may help reverse the loss of proteintypically seen in alcohol-dependent patients.

ii. Diet (120 b)

Depending upon the results of the initial examination, a universal orpatient-specific diet plan may optionally be administered in conjunctionwith the methodology.

iii. Exercise (120 c)

Depending upon the results of the initial examination, a universal orpatient-specific exercise programs may optionally be administered inconjunction with the methodology.

iv. Inpatient Therapy (120 d)

A structured program for cognitive behavior therapy is preferablyimplemented in the methodology. Individual psychotherapy is focused on aplurality of interventions, such as cognitive restructuring, worktherapy, prevention of relapse, and stress reduction aimed atrehabilitating the social, family, work, personal and leisure life ofthe patient.

c. Post-Treatment (130)

Referring back to FIG. 1, after a patient successfully completes theduring treatment phase of the methodology of the present invention 100,each patient will be prescribed a post-treatment regimen 130 to follow,which includes, but is not limited to, the administration ofpharmaceutical compositions 130 a, a CIWA assessment 130 b, outpatienttherapy 130 c, a diet program 130 d, and an exercise regimen 130 e. Thecomponents of the post-treatment phase of the methodology of the presentinvention 100 are described in greater detail below.

i. Pharmaceutical Compositions (130 a)

Before discharge from the hospital, one or more of the followingcompositions or drugs are prescribed. Preferably, the compositions ordrugs can be administered in oral form to enable greater patientcompliance and convenience. It should be appreciated that, to the extentany of drugs described herein are not available in the jurisdiction inwhich this invention is being practiced, equivalent functioning drugsmay be used.

1. Vitamin B

a. Fortified Vitamin B Complex

Chronic alcohol consumption depletes the levels of several vitamins,particularly the B vitamins (also known as the stress vitamins). Thesevitamins are required by the body to convert food into energy, maintainthe integrity of tissues such as the skin and liver, and combat physicalor emotional stress. Administration of vitamin B complex as part of themanagement of the alcohol-dependent patient may help to ameliorate therisk of Wernicke-Korsakoff syndrome and alcoholism-induced cognitivedeficit. The present invention preferably includes the provision of anutritional supplement of fortified vitamin B-complex (thiamine—B1,riboflavin—B2, niacin—B3, pyridoxine—B6, folic acid—B9,cyanocobalamin—B12, pantothenic acid, and biotin) to patients dailyduring stabilization with the methodology and post-discharge for as longas medically beneficial.

b. IV Vitamin B Supplement

Alcohol abusers tend to have poor nutritional status, exacerbated bypoor diet, gastritis, duodenitis, frequent vomiting, physical illness,and weight loss. Thus, there is a need for parenteral vitamins. Thiamineabsorption from oral treatment tends to vary; alcohol in the gutinterferes with absorption. Thus, there is a potentially large thiaminedeficiency in alcohol dependence. Oral dosing is unlikely to meetmaintenance requirements. Thiamine decreases sodium transport in alcoholdependence. In addition, it is a catalyzer of key metabolic actions ofGABA.

2. Piracetam

Piracetam is a CNS (central nervous system) stimulant with no knowntoxicity or addictive properties. Piracetam is used as a supplement toimprove cognitive functioning in patients suffering from alcoholwithdrawal. Piracetam is preferably prescribed in the following dosagesfor this methodology: 3 grams every morning for one week, followed by800 mg twice daily for one month.

3. Fluoxetine

Fluoxetine hydrochloride is an antidepressant for oral administration;it is chemically unrelated to tricyclic, tetracyclic, or other availableantidepressant agents. It is designated(±)-N-methyl-3-phenyl-3-[(a,a,a-trifluoro-p-tolyl)-oxy]propylaminehydrochloride. As part of this methodology, it is used to treat symptomsof anxiety and depression associated with alcohol and/or psychostimulantdependence. The suggested dosage is 10 to 20 mg of fluoxetine everymorning for two months, but may be increased or decreased on a perpatient basis.

4. Clomethiazole

The suggested dosage of clomethiazole (or chlormethiazole) is about 200mg, and more specifically about 192 mg, in both the morning and eveningfor 1 week and eliminated during the second week.

5. Disulfuram

Disulfuram, an inhibitor of aldehyde dehydrogenase in the liver,increases blood acetaldehyde concentrations and subsequently inducessymptoms of acetaldehyde syndrome, including (but not limited to)vomiting, weakness, confusion, vasodilation in the head, and throbbingheadache. This agent is used in the methodology for six monthspost-discharge to induce averse associations with alcohol consumption,thus helping to sustain the recovery process. In one embodiment, thedosage is 250 mg every morning as long as medically beneficial.

6. Gabapentin

a. Use of Gabapentin

Gabapentin is an anxiolytic and anticonvulsant medication typicallyprescribed to patients suffering from epilepsy (effectively lowers brainglutamate concentrations) and can be used in the treatment of anxietydisorders such as social anxiety disorder and obsessive-compulsivedisorder. Gabapentin compliments flumazenil in helping normalize GABAand glutamate transmission, thus enhancing GABA tone.

Gabapentin was originally designed as a structural analog of GABA. Itlikely operates as a calcium N-channel blocker. Gabapentin also exhibitspost-synaptic effects modulating NMDA-mediated transmission by 1)reducing NMDA/Glutamatergic tone and 2) indirectly helping compensatefor reduced GABAergic tone due to upregulated NMDA activity in thewithdrawn state. Gabapentin can provide for an improved quality andquantity of sleep and an improved anxiety state. As a result of itsabove-mentioned qualities, gabapentin decreases withdrawal symptoms.

b. Key Pharmacologic Safety Considerations for the Use of Gabapentin

Prior to administering gabapentin to a patient, it is essential toassess the patient for interactions and contraindications. Gabapentin isto be used in adjunctive therapy in the treatment of epilepsy seizures(partial) and for the management of postherpetic neuralgia. Gabapentinis not appreciably metabolized and is excreted unchanged with anelimination half-life of 5-7 hours. Possible side effects from the useof gabapentin are dizziness, somnolence, other symptoms/signs of CNSdepression, nausea, ataxia, tremor, and peripheral edema. In personswith epilepsy, abrupt discontinuation may increase seizure frequency. Noclinically significant drug interactions have been reported in theliterature.

7. Other Drugs

Optionally, after the final Selective Chloride Channel Modulatoradministration, non-stimulant drugs can be administered. Specifically,after the final flumazenil treatment, non-benzodiazepine, barbituratedrugs or drugs with a direct chloride channel effect can beadministered.

ii. Withdrawal Symptomatology (130 b)

Before and after the administration of flumazenil, the withdrawalsymptomatology should be measured using the CIWA-A evaluation (Adinoffet al., Medical Toxicology 3:172-196 (1988)), as well as heart rate andblood pressure.

iii. Outpatient Therapy (130 c)

Psychotherapy/behavioral therapy and counseling may be critical for thesuccess of alcohol and/or stimulant substance-dependency treatment whenadopting a pharmacological approach. Thus, the methodology also providesfor a maintenance program that includes medications and incentives forthe patient to continue with their recovery process through continuingcare programs. The methodology is not considered a replacement forbehavioral therapy and is not a cure. Due to the complexity of alcoholand/or stimulant substance dependence, patients benefit most from acombination of pharmacologic and behavioral interventions.

As part of the treatment program, patients are preferably instructed toattend the outpatient treatment center for 9 months with decreasingfrequency [once a week for the first three months, once every two weeksduring the second three months, and once a month during the third threemonths].

Likewise, a semi-structured follow-up of cognitive behavior therapy ispreferably implemented. Individual and family psychotherapy is focusedon a plurality of interventions, including cognitive restructuring, worktherapy, prevention of relapse, and stress reduction, aimed atrehabilitating the social, family, work, personal and leisure life ofthe patient.

iv. Diet (130 d)

Depending upon the results of the initial examination, a universal orpatient-specific diet plan may optionally be administered in conjunctionwith the methodology.

v. Exercise (130 e)

Depending upon the results of the initial examination, a universal orpatient-specific exercise programs may optionally be administered inconjunction with the methodology.

3. Methodology Embodiments

Reference will now be made in detail to specific embodiments andexamples of the methods and protocols of the present invention. Whilethe invention will be described in conjunction with specificembodiments, it is not intended to limit the invention to oneembodiment. In addition, many combinations of the methodology componentsdescribed above are possible; thus, the invention is not limited to suchexamples as provided.

In one specific embodiment, the present invention relates to the use ofa therapeutically effective quantity of a drug, namely a SelectiveChloride Channel Modulator, such as, but not limited to, flumazenil, ina methodology for treatment of alcohol and/or psychostimulantdependency. More specifically, the invention relates to the use offlumazenil in multiple doses for a predetermined time period as part ofthe treatment methodology. When administered in accordance with thepresent invention, a therapeutically effective amount of the drug ismaintained in the patient, thereby significantly reducing cravings foralcohol. The methodology of the present invention also provides for theadministration of flumazenil without significant side effects.

Thus, in one embodiment, a method is provided for the treatment ofalcohol and/or psychostimulant abuse that includes the administration toa patient in need of said treatment of a therapeutically effectivequantity of flumazenil between 0.5 mg/day and 10 mg/day, specificallybetween 1.0 and 3.0 mg/day, and even more specifically between 1.5 and2.5 mg/day, broken down into multiple doses of flumazenil between 0.2and 0.3 mg and intended for administration during predetermined timeperiods or intervals, until said therapeutically effective quantity offlumazenil to treat alcohol and/or psychostimulant dependency has beenreached. In one embodiment, the predetermined time period is in therange of 1 and 15 minutes and the “per dose” quantity of flumazenil isbetween 0.1 and 0.3 mg.

One of ordinary skill in the art would appreciate that the individualdoses can range in amount, and the time interval between the individualdoses can range in amount, provided that the total dose delivered is inthe range of 0.5 mg/day and 10.0 mg/day and the individual doses aredelivered at relatively consistent time intervals. Therefore, the timeperiod intervals can range from 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12,13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, or 25 minutes orfractions thereof. Doses delivered at each time period, separated by thetime intervals, can be between 0.1 and 0.3 mg, or fractions thereof,keeping in mind the total drug delivered is preferably less than 10.0mg/day. The present invention therefore provides for the delivery ofmultiple, sequential doses, delivered at substantially consistent timeintervals.

Conventional uses of flumazenil comprise either singular doses or muchlarger doses over shorter periods of time and are directed towardaddressing anesthesia, conscious sedation, or benzodiazepine overdose.Further, Romazicon, a brand name for flumazenil as marketed and sold byRoche, is expressly indicated to complicate the management of withdrawalsyndromes for alcohol, barbiturates and cross-tolerant sedatives and wasshown to have an adverse effect on the nervous system, causing increasedagitation and anxiety. For a single dose to address anesthesia andconscious sedation, it is conventionally recommended to use a dose of0.2 mg to 1 mg of Romazicon with a subsequent dose in no less than 20minutes. For repeat treatment, 1 mg doses may be delivered over fiveminutes up to 3 mg doses over 15 minutes. In benzodiazepine overdosesituations, a larger dose may be administered over short periods oftime, such as 3 mg doses administered within 6 minutes. One of ordinaryskill in the art would appreciate that, relative to the presentinvention, this dosing regimen either fails to maintain a presence offlumazenil in the bloodstream for extended periods of time (over a 12 to24 hour period) or presents excessive amounts of flumazenil at any giventime. Moreover, such conventional uses of flumazenil are not directedtoward the treatment of alcohol or stimulant dependence.

In the treatment methodology of the present invention, flumazenil can besafely administered to patients in small quantities, applied in multipledoses during predetermined time periods/intervals, until atherapeutically effective quantity of flumazenil to treat alcohol and/orpsychostimulant dependency has been reached. Thus, it is possible toadminister flumazenil in smaller doses to obtain the desired therapeuticresponse, reducing the risk of secondary effects in the patient (as aresult of reducing the quantity of drug administered per dose applied).

In addition, the administration method of the present invention providesa better use of flumazenil to treat the symptoms of alcohol and/orpsychostimulant withdrawal and to reduce the unnecessary consumption ofsaid drug, thereby increasing convenience and the quality of life of thepatient and reducing cost, to treat alcohol and/or psychostimulantdependency in a very short period of time.

The method for the treatment of alcohol dependency provided by thisinvention is applicable to any patient who, when the treatment is tobegin, has no acute or uncompensated illness, or is not takingmedication contraindicated with the Selective Chloride ChannelModulator, such as flumazenil. In general, the method of treatment ofalcohol and/or psychostimulant dependency provided by this inventionbegins with a complete medical and psychological examination, asdescribed in detail above. Before and after administration offlumazenil, the symptoms of alcohol withdrawal, heart rate, and bloodpressure are evaluated. If the patient presents with mild to moderateanxiety, it is possible to administer an appropriate therapeutic agent,for example, clomethiazole, before administration of flumazenil, asdescribed above.

Once inpatient treatment has concluded, as part of the therapeuticprogram, the patient must continue pharmacological treatment andcontinue sessions with his therapist to evaluate his progress. Thetreatment is supplemented by a semi-structured therapy regime to monitorthe cognitive behavior of the patient. According to another embodiment,alcohol dependent patients may be treated on an outpatient basis for 48hours.

While references above have been made to inpatient treatment, it shouldbe appreciated that an outpatient treatment regimen is possible,provided that the patient criteria is met, as previously described. Itshould further be appreciated that in both outpatient and inpatienttreatment methodologies, Clinical Inventory Withdrawal Assessments(CIWA-Ar) should be utilized for assessment of withdrawal.

For example, for inpatient alcohol dependency treatment, the followingCIWA evaluation guide can be used:

TABLE 1 Inpatient Alcohol CIWA-Ar Evaluation Guide Pre-admission CIWA-ArTransfer to appropriate medical Screening facility for detoxification ifscore is ≧15, and/or if acute medical or psychiatric problems arepresent. Day 1 (a.m. of CIWA-Ar Transfer to appropriate medicalpotential facility for detoxification if score admission) is ≧15, and/orif acute medical or psychiatric problems are present. Day 1 Pre- CIWA-ArTrack CIWA-Ar scores to determine infusion direction and potentialacceleration of scores. Day 1 Post- CIWA-Ar Track CIWA-Ar scores todetermine infusion direction and potential acceleration of scores. Day 19pm^(1.) CIWA-Ar Day 3 required if CIWA ≧10 Day 2 Pre- CIWA-Ar Day 3required if CIWA ≧10 infusion^(1.) Day 2 Post- CIWA-Ar Day 3 required ifCIWA >6. Also can infusion^(1.) serve as discharge evaluation. ¹Apatient meeting any one of these scores requires a 3^(rd) treatment.

For outpatient alcohol dependency treatment, the following CIWAevaluation guide can be used:

TABLE 2 Outpatient Alcohol CIWA-Ar Evaluation Guide Screening CIWA-ArRecommend in-patient treatment if score is ≧6 but not greater than 15.Transfer to appropriate medical facility for detoxification if score is≧15, and/or if acute medical or psychiatric problems are present. Day 1CIWA-Ar Transfer to appropriate medical (a.m. of facility fordetoxification if score potential is ≧15, and/or if acute medical oradmission) psychiatric problems are present. Day 1 Post- CIWA-Ar Dailydischarge criteria requires a infusion CIWA-Ar score of less than 6. Day2 Post- CIWA-Ar Daily discharge criteria requires a infusion CIWA-Arscore of less than 6.

Now referring to FIG. 2, in a first exemplary methodology 200 fortreating alcohol withdrawal, a patient undergoes the aforementionedpre-treatment regimen 210, which may include a complete physicalexamination 210 a, a complete psychological examination 210 b, a CIWAassessment 210 c, and determination of required medications 210 d.

On day 1 220 a of treatment phase 220, the patient receivespharmaceutical compositions 221 a, including flumazenil via anintravenous infusion, ultimately delivering a total amount of 2 mg perdosing interval. The patient further receives 50 mg of hydroxyzine twicedaily plus or minus 25 mg as may be required. The patient furtherreceives fortified vitamin B complex daily and a protein supplementdrink daily in the morning.

On day 2 220 b of treatment, the patient receives pharmaceuticalcompositions 221 b, including flumazenil via an intravenous infusion,ultimately delivering a total amount of 2 mg per dosing interval. Thepatient further receives 50 mg of hydroxyzine twice daily plus or minus25 mg as may be required. The patient further receives fortified vitaminB complex daily and a protein supplement drink daily in the morning.

Also during treatment, the patient may be prescribed a diet plan 222,exercise regiment 223, and inpatient therapy 224.

In the post-treatment phase 230 after discharge, for one week, thepatient receives various pharmaceutical compositions 230 a, including 50mg of hydroxyzine at bedtime or for sleep and, for a subsequent week,the patient receives 25 mg of hydroxzine at bedtime or for sleep. Fortwo weeks, the patient also receives glutamine titrated up to 1500 mgper day and fortified vitamin B complex daily. The patient may alsoreceive additional post-treatment options, including a CIWA Assessment230 b, outpatient therapy 230 c, and a diet and exercise regimen 230 d,230 e.

Referring now to FIG. 3, in a second exemplary methodology for treatingalcohol withdrawal 300, a patient undergoes the aforementionedpre-treatment regimen 310, which may include a complete physicalexamination 310 a, a complete psychological examination 310 b, a CIWAassessment 310 c, and a determination of required medications 310 d.

On day 1 330 a of treatment phase 330, the patient receives variouspharmaceutical compositions 321 a, including flumazenil via anintravenous infusion, ultimately delivering a total amount of 2 mg perdosing interval. The patient further receives 50 mg of hydroxyzineduring the day and 50 mg of hydroxyzine at bedtime or in the evening.The patient further receives IV Vitamin B Complex and oral Gabapentin ata dose of 300 mg.

On day 2 330 b of treatment phase 330, the patient receives variouspharmaceutical compositions 321 b, including flumazenil via anintravenous infusion, ultimately delivering a total amount of 2 mg perdosing interval. The patient further receives 50 mg of hydroxyzineduring the day and 50 mg of hydroxyzine at bed or in the evening. Thepatient further receives IV Vitamin B Complex and oral Gabapentin at adose of 300 mg in the afternoon and evening or at bedtime.

In addition, during treatment phase 320, a patient may be prescribed adiet plan 322, an exercise regimen 323, and inpatient therapy 324.

After discharge, for days one and two of post-treatment phase 330, thepatient receives pharmaceutical compositions 330 a, including 50 mg ofhydroxyzine at bedtime or in the evening. For 30 days, the patientreceives Gabapentin at a dose of 900 mg in the afternoon and evening orat bedtime then titrating down to 0. For one week, the patient alsoreceives vitamin B 100 daily. The patient may also optionally receive aCIWA assessment 330 b, outpatient therapy 330 c, a diet plan 330 d, andan exercise regiment 330 e.

Referring now to FIG. 4, in a third exemplary methodology for treatingalcohol withdrawal 400, a patient undergoes the aforementionedpre-treatment regimen 410, which may include a complete physicalexamination 410 a, a complete psychological examination 410 b, a CIWAassessment 410 c, and a determination of required medications 410 d.

During treatment phase 420, the patient undergoes a pre-treatmentprocedure 421 that includes a CIWA assessment and the administration ofhydroxyzine at a dose of 50 mg. On day one 422 a of treatment phase 420,a first infusion 423 a is administered to the patient. The firstinfusion includes vitamin B1, vitamin B6, vitamin B12, and vitamin Bcomplex and 2 mg of flumazenil over a period of 2 hours. After the firstinfusion, the patient undergoes a post-treatment procedure 424,typically in the late afternoon to evening that includes a CIWAassessment, the administration of Gabapentin at a dose of 300 mg, andthe administration of hydroxyzine at a dose of 50 mg in the evening orbedtime.

On day two 422 b of treatment phase 420, a patient undergoes apre-treatment procedure 421 that includes a CIWA assessment and theadministration of hydroxyzine at a dose of 50 mg. A second infusion 423b is then administered to the patient. The second infusion includesvitamin B1, vitamin B6, vitamin B12, and vitamin B complex and 2 mg offlumazenil over a period of 2 hours. After the second infusion, thepatient undergoes a post-treatment procedure 424, typically in the lateafternoon to evening that includes a CIWA assessment, the administrationof Gabapentin at a dose of 300 mg, and the administration of hydroxyzineat a dose of 50 mg in the evening or bedtime.

During treatment phase 420 may also optionally include a diet plan 425,an exercise regimen 426, and inpatient therapy 427.

After discharge, the patient is monitored based on the CIWA assessment430 b and the patient's medical condition. Optionally, prior todischarge, the patient undergoes a third day 422 c of treatment 420 thatis similar to day 2 422 b, if warranted by the patient's medicalcondition and/or CIWA assessment.

At discharge, in post-treatment phase 430, the patient is givenpharmaceutical compositions 430 a, which include 50 mg of hydroxyzine ondays 1 and 2 at bedtime. The patient is also given gabapentin in thefollowing amounts: 300 mg on day 1; 600 mg on day 2; and on days 3-30,900 mg titrated down to zero. The patient is also given an Oral VitaminB 100 complex daily for one week. Optionally, the patient may beprescribed outpatient therapy 430 c, a diet plan 430 d, and an exerciseregimen 430 e.

Referring now to FIG. 5, in a first exemplary methodology for treatingstimulant withdrawal 500, a patient undergoes the aforementionedpre-treatment regimen 510. Pre-treatment regimen 510 may include acomplete physical examination 510 a, a complete psychologicalexamination 510 b, a CIWA assessment 510 c, and a determination ofrequired medications 510 d.

On day 1 520 a, day 2 520 b and day 3 520 c of treatment phase 520, thepatient receives pharmaceutical compositions 521, including flumazenilvia an intravenous infusion, ultimately delivering a total amount of 2mg per dosing interval. The patient further receives 50 mg ofhydroxyzine twice daily plus or minus 25 mg as may be required. Thepatient further receives fortified vitamin B complex daily and a proteinsupplement drink daily in the morning.

This treatment regimen 520, preferably day 1 520 a and day 2 520 b only,is repeated after three weeks 522. During both phases of the treatmentphase 520, the patient may be prescribed a diet plan 523, an exerciseregimen 524, and inpatient therapy 525.

In post-treatment phase 530, after discharge, the patient receivespharmaceutical compositions 530 a, which include 50 mg of hydroxyzine atbedtime or for sleep for one week and, for a subsequent week, 25 mg ofhydroxyzine at bedtime or for sleep. For two weeks, the patient alsoreceives glutamine titrated up to 1500 mg per day and fortified vitaminB complex daily. The patient further receives Gabapentin titrated up to1200 mg per day for six months. This regimen is interrupted for a secondround of treatments 522, as described above, after three weeks haveelapsed from the first round of treatments and restarted thereafter.

Now referring to FIG. 6, in a second exemplary methodology for treatingstimulant withdrawal 600, a patient undergoes the aforementionedpre-treatment regimen 610. Pre-treatment regimen 610 may include acomplete physical examination 610 a, a complete psychologicalexamination 610 b, a CIWA assessment 610 c, and a determination ofrequired medications 610 d.

On day 1 620 a, day 2 620 b and day 3 620 c of treatment phase 620, thepatient receives pharmaceutical compositions 621, including flumazenilvia an intravenous infusion, ultimately delivering a total amount of 2mg per dosing interval. The patient further receives 50 mg ofhydroxyzine. The patient further receives fortified vitamin B complexdaily and Gabapentin at a dose of 300 mg.

This treatment regimen 620, preferably day 1 620 a and day 2 620 b only,is repeated after three weeks 622. During both phases of the treatmentphase 620, the patient may be prescribed a diet plan 623, an exerciseregimen 624, and inpatient therapy 625.

In post-treatment phase 630, after discharge, the patient receivespharmaceutical compositions 630 a, which include gabapentin titrated upto 400 mg per day for 30 days, decreasing to 0. The patient alsoreceives fortified vitamin B 100 complex daily and a plurality of aminoacid supplements. This regimen is interrupted for a second round oftreatments, as described above, after three weeks have elapsed from thefirst round of treatments and restarted thereafter. Duringpost-treatment 630, the patient may also undergo CIWA assessment 630 bas needed, outpatient therapy 630 c, a diet plan 630 d, and an exerciseregimen 630 e.

In another exemplary methodology, a patient is treated on an inpatientbasis for alcohol dependence. Preferably, in this treatment methodology,the interval between treatment episodes, implemented in a series, shouldbe no less than 12 hours and no greater the 24 hours. Depending on apatient's progress with the treatments, he or she may require anadditional treatment requiring that would take place on day three ofhis/her inpatient stay, as described above in an exemplary CIWA-ArEvaluation Guide.

On day one, the patient is administered 50 mg of hydroxyzine HCL 50p.o., unless otherwise contraindicated. After at least one-hour, theSelective Chloride Channel Modulator, such as flumazenil, isadministered. Prior to Selective Chloride Channel Modulator infusion,two infusion bags are prepared. The first infusion bag comprises 500 cc½ normal saline (NS) to which thiamine, pyridoxine and other vitamincomponents are added and the second infusion bag comprises 500 cc ½ NSfor clearing the line and for subsequent Selective Chloride ChannelModulator administration. 100 mg of thiamine, 25 mg of pyridoxine, and 5cc of MVI is preferably added to the first infusion bag. The firstinfusion bag is administered to the patient at 125 cc/hr (NTE 150cc/hour) by placing the IV in the antecubital fossa. The IV line shouldfurther include the use of a stopcock for clearing of the line andsubsequent administration of the Selective Chloride Channel Modulator.Using the stopcock, the line should be washed out with the ½ NS until nofurther color is seen in the line going to the patient.

Once the line is washed, the Selective Chloride Channel Modulatoradministration can be initiated. Where the Selective Chloride ChannelModulator is flumazenil, a total dose of 2 mg is given at each treatmentepisode. The medication should be given by IV bolus as follows: a) 0.1mg every 3 minutes for two doses, b) 0.2 mg every 3 minutes for twodoses; and c) 0.3 mg every 2 minutes until the total dose of 2 mg hasbeen given. If, when increasing dose or decreasing time between doses,discomfort of any kind is observed or reported, the drug administrationshould be returned to the pre-discomfort level or even returned toinitial levels. In one embodiment, the total dose of flumazeniladministration is 4 mg for alcohol dependence (two treatment episodes)and 6 mg for patients requiring an additional treatment (e.g. oninpatient day # 3). Parameters of flumazenil administration could bemodified in some cases. Quantities can be higher than the 2 mg dose orcan be higher than 0.3 mg per administration. Additionally, time periodsbetween administrations can be increased or decreased slightly. Once theflumazenil administration is complete, the vitamin infusion can bereinitiated once the line is cleared with ½ NS. The patient should bemonitored for 3 hours post flumazenil administration during which timerepeat CIWA-Ar assessments should be performed.

Provided in Tables 3 and 4 below are further details on this specificmethodology example.

TABLE 3 Alcohol Dependence Treatment Methodology During 2 Day In-PatientStay Day 1 Day 1 Day 2 Day 2 Post-discharge Time (Admission Day) Time(Discharge) medications 30 minutes Negative Urine  1 hour HydroxyzineHCL 50 mg Hydroxyzine HCL: 50 mg po hs toxicology. po for one WeekPre-treatment Medical Continue Observation Gabapentin: Begin dayAssessment & Monitoring for AWS following discharge 900 mg po MVI/12,Thiamine, hs for 30 days then titrate Pyridoxine IV down to 0 days 31-37((600 mg 150 cc, NTE 150 cc/hr. for 3 days, 300 mg for 3 days) FortifiedVitamin B Complex: 100 mg po for one Week  1 hour Hydroxyzine HCL 50 mg30 mins. Flumazenil 2 mg IVP po per administration MVI/12, Thiamine,schedule Pyridoxine IV NTE 150 cc/hr. 30 mins. Flumazenil 2 mg IVP  3hours MVI/12, Thiamine, per administration Pyridoxine IV schedule NTE150 cc/hr. (Total vitamin infusion of 250 cc-500 cc) ContinueObservation & Monitoring Gabapentin 600 mg po  3 hours MVI/12, Thiamine,May discharge if Pyridoxine IV CIWA-AR <6 NTE 150 cc/hr. (TotalDischarge w/ vitamin infusion of medication 250 cc-500 cc) instructionsand Continue Observation continuing care & Monitoring recommendationsBedtime Gabapentin 300 mg po If day 3 needed: no later than 21:00 hrs.See inpatient alcohol but after CIWA- CIWA-Ar Evaluation Ar assessmentGuide to determine Hydroxyzine HCL 50 mg need for 3^(rd) day. If po @bedtime may 3^(rd) day needed, refer repeat with 25 mg as to Table 4below needed for sleep

TABLE 4 Alcohol Dependence Treatment Methodology During 3 day In-PatientStay Day 1 Day 1 (Admission Day 2 Day 3 Day 3 Post-discharge Time Day)Time Day 2 Time (Discharge) medications 30 mins. Negative  1 hourHydroxyzine  1 hour Hydroxyzine Hydroxyzine HCL: Urine HCL 50 mg po HCL50 mg po 50 mg po hs for toxicology Continue Continue one week Pre-Observation & Observation & Gabapentin: treatment Monitoring forMonitoring Begin day Medical AWS for AWS following Assessment MVI/12,MVI/12, discharge 900 mg Thiamine, Thiamine, po hs for 30 Pyridoxine IVPyridoxine IV days then 150 cc, NTE 150 cc/hr. 150 cc, NTE titrate downto 150 cc/hr. 0 days 31-37 ((600 mg for 3 days, 300 mg for 3 days)Fortified Vitamin B Complex: 100 mg po for One Week  1 hour Hydroxyzine30 mins. Flumazenil 2 mg 30 mins. Flumazenil 2 mg HCL 50 mg po IVP IVPMVI/12, per per Thiamine, administration administration Pyridoxineschedule schedule IV NTE 150 cc/hr. 30 mins. Flumazenil 2 mg  3 hoursMVI/12,  3 hours MVI/12, IVP per Thiamine, Thiamine, administrationPyridoxine IV Pyridoxine IV schedule NTE 150 cc/hr. NTE 150 cc/hr.(Total vitamin (Total infusion of vitamin 250 cc-500 cc) infusion ofContinue 250 cc-500 cc) Observation & Continue Monitoring Observation &Monitoring Gabapentin 900 mg po 3 hours MVI/12, Discharge w/ Thiamine,medication Pyridoxine instructions IV and NTE 150 cc/hr. continuing(Total care vitamin recommendations infusion of 250 cc-500 cc) ContinueObservation & Monitoring Bedtime Gabapentin Bedtime Gabapentin 600 mg300 mg po no po no later later than than 21:00 hrs. 21:00 hrs. but afterbut after CIWA-Ar CIWA-Ar assessment assessment Hydroxyzine HydroxyzineHCL 50 mg po @ HCL 50 mg po bedtime may @ bedtime repeat with 25 mg mayrepeat as needed with 25 mg for sleep as needed for sleep

In another exemplary methodology, a patient is treated on an outpatientbasis for alcohol dependence. Preferably, in this treatment methodology,the interval between treatment episodes, implemented in a series, shouldbe no less than 12 hours and no greater the 24 hours.

On day one, the patient is administered 50 mg of hydroxyzine HCL 50p.o., unless otherwise contraindicated. After at least one-hour, theSelective Chloride Channel Modulator, such as flumazenil, isadministered. Prior to Selective Chloride Channel Modulator infusion,two infusion bags are prepared. The first infusion bag comprises 500 cc½ normal saline (NS) to which thiamine, pyridoxine and other vitamincomponents are added and the second infusion bag comprises 500 cc ½ NSfor clearing the line and for subsequent Selective Chloride ChannelModulator administration. 100 mg of thiamine, 25 mg of pyridoxine, and 5cc of MVI is preferably added to the first infusion bag. The firstinfusion bag is administered to the patient at 125 cc/hr (NTE 150cc/hour) by placing the IV in the antecubital fossa. The IV line shouldfurther include the use of a stopcock for clearing of the line andsubsequent administration of the Selective Chloride Channel Modulator.Using the stopcock, the line should be washed out with the ½ NS until nofurther color is seen in the line going to the patient.

Once the line is washed, the Selective Chloride Channel Modulatoradministration can be initiated. Where the Selective Chloride ChannelModulator is flumazenil, a total dose of 2 mg is given at each treatmentepisode. The medication should be given by IV bolus as follows: a) 0.1mg every 3 minutes for two doses, b) 0.2 mg every 3 minutes for twodoses; and c) 0.3 mg every 2 minutes until the total dose of 2 mg hasbeen given. If, when increasing dose or decreasing time between doses,discomfort of any kind is observed or reported, the drug administrationshould be returned to the pre-discomfort level or even returned toinitial levels. In one embodiment, the total dose of flumazeniladministration is 4 mg for alcohol dependence (two treatment episodes).Parameters of flumazenil administration could be modified in some cases.Quantities can be higher than the 2 mg dose or can be higher than 0.3 mgper administration. Additionally, time periods between administrationscan be increased or decreased slightly. Once the flumazeniladministration is complete, the vitamin infusion can be reinitiated oncethe line is cleared with ½ NS. The patient should be monitored for 3hours post flumazenil administration during which time repeat CIWA-Arassessments should be performed.

Provided in Table 5 below are further details on this specificmethodology example.

TABLE 5 Alcohol Dependence Treatment Methodology During 2 DayOut-Patient Stay Day 1 Day 2 Final discharge Time Day 1 Time Day 2medications 30 mins. Negative Urine  1 hour Hydroxyzine HCL HydroxyzineHCL: toxicology. 50 mg po 50 mg po hs for One Pre-treatment ContinueWeek Medical Assessment Observation & Gabapentin: Begin Monitoring dayfollowing final MVI/12, Thiamine, discharge 900 mg po Pyridoxine IV hsfor 30 days then 150 cc, NTE 150 cc/hr. titrate down to 0 days 31-37((600 mg for 3 days, 300 mg for 3 days) Fortified Vitamin B Complex: 100mg po for One Week  1 hour Hydroxyzine HCL 30 mins. Flumazenil 2 mg IVP50 mg po per administration MVI/12, Thiamine, schedule Pyridoxine IV NTE150 cc/hr. 30 mins. Flumazenil 2 mg IVP  3 hours MVI/12, Thiamine, peradministration Pyridoxine IV schedule NTE 150 cc/hr. (Total vitamininfusion of 250 cc-500 cc) Continue Observation & Monitoring Gabapentin600 mg po  3 hours MVI/12, Thiamine, May discharge if Pyridoxine IVCIWA-AR <6 NTE 150 cc/hr. Discharge w/ (Total vitamin medicationinfusion of 250 cc-500 cc) instructions and Continue continuing careObservation & recommendations Monitoring May discharge if CIWA-AR <6Discharge w/ medication instructions and scheduled time for day 2treatment Bedtime Gabapentin 300 mg po no later than 21:00 hrs.Hydroxyzine HCL 50 mg po @ bedtime may repeat with 25 mg as needed forsleep

In another exemplary methodology, a patient is treated on an inpatientor outpatient basis for stimulant dependence. Preferably, in thistreatment methodology, the interval between treatment episodes,implemented in a series, should be no less than 12 hours and no greaterthe 24 hours.

On day one, the patient is administered 50 mg of hydroxyzine HCL 50p.o., unless otherwise contraindicated. After at least one-hour, theSelective Chloride Channel Modulator, such as flumazenil, isadministered. Prior to Selective Chloride Channel Modulator infusion,two infusion bags are prepared. The first infusion bag comprises 500 cc½ normal saline (NS) to which thiamine, pyridoxine and other vitamincomponents are added and the second infusion bag comprises 500 cc ½ NSfor clearing the line and for subsequent Selective Chloride ChannelModulator administration. 100 mg of thiamine, 25 mg of pyridoxine, and 5cc of MVI is preferably added to the first infusion bag. The firstinfusion bag is administered to the patient at 125 cc/hr (NTE 150cc/hour) by placing the IV in the antecubital fossa. The IV line shouldfurther include the use of a stopcock for clearing of the line andsubsequent administration of the Selective Chloride Channel Modulator.Using the stopcock, the line should be washed out with the ½ NS until nofurther color is seen in the line going to the patient.

Once the line is washed, the Selective Chloride Channel Modulatoradministration can be initiated. Where the Selective Chloride ChannelModulator is flumazenil, a total dose of 2 mg is given at each treatmentepisode. The medication should be given by IV bolus as follows: a) 0.1mg every 3 minutes for two doses, b) 0.2 mg every 3 minutes for twodoses; and c) 0.3 mg every 2 minutes until the total dose of 2 mg hasbeen given. If, when increasing dose or decreasing time between doses,discomfort of any kind is observed or reported, the drug administrationshould be returned to the pre-discomfort level or even returned toinitial levels. In one embodiment, the total dose of flumazeniladministration is 6 mg for the first treatment cycle (three treatmentepisodes) and 4 mg for the second treatment cycle (two treatmentepisodes). Parameters of flumazenil administration could be modified insome cases. Quantities can be higher than the 2 mg dose or can be higherthan 0.3 mg per administration. Additionally, time periods betweenadministrations can be increased or decreased slightly. Once theflumazenil administration is complete, the vitamin infusion can bereinitiated once the line is cleared with ½ NS. The patient should bemonitored for 3 hours post flumazenil administration during which timerepeat CIWA-Ar assessments should be performed.

Provided in Tables 6 and 7 below are further details on this specificmethodology example.

TABLE 6 Stimulant Dependence Treatment Methodology Cycle 1 - During 3day In-Patient/Out-Patient Stay Day 1 Day 1 (Admission Day 2 Day 3Post-discharge Time Day) Time Day 2 Time Day 3 medications 30 mins.Negative  1 hour Hydroxyzine  1 hour Hydroxyzine Hydroxyzine HCL: UrineHCL 50 mg po HCL 50 mg po 50 mg po hs for one toxicology. ContinueContinue week Pre- Observation & Observation & Gabapentin: Begintreatment Monitoring Monitoring day following Medical MVI/12, MVI/12,discharge 900 mg po Assessment Thiamine, Thiamine, hs for 2 days andPyridoxine IV Pyridoxine days 3 to evening 150 cc, NTE IV beforetreatment 150 cc/hr. 150 cc, NTE cycle 2 1200 mg 150 cc/hr. po hsFortified Vitamin B Complex: 100 mg po for One Week  1 hour Hydroxyzine30 mins. Flumazenil 2 mg 30 mins. Flumazenil HCL 50 mg po IVP 2 mg IVPMVI/12, per admin. per admin. Thiamine, schedule schedule Pyridoxine IVNTE 150 cc/hr. 30 mins. Flumazenil 2 mg  3 hours MVI/12,  3 hoursMVI/12, IVP per Thiamine, Thiamine, admin. Pyridoxine IV Pyridoxineschedule NTE 150 cc/hr. IV (Total NTE 150 cc/hr. vitamin (Total infusionof vitamin 250 cc-500 cc) infusion of Continue 250 cc-500 cc)Observation & Continue Monitoring Observation & Gabapentin Monitoring600 mg po Gabapentin 600 mg po  3 hours MVI/12, Discharge Thiamine, w/Pyridoxine medication IV instruction NTE 150 cc/hr. and (Totalcontinuing vitamin care infusion of recommend. 250 cc-500 cc) ContinueObservation & Monitoring Bedtime Gabapentin 300 mg po no later than21:00 hrs. Hydroxyzine HCL 50 mg po @ bedtime may repeat with 25 mg asneeded for sleep

TABLE 7 Stimulant Dependence Treatment Methodology Cycle 2 - During 2day In-Patient/Out-Patient Stay Day 1 Day 1 (Admission Day 2 Day 2 TimeDay) Time (Discharge) Post-discharge medications 30 mins. Negative  1hour Hydroxyzine HCL 50 mg Gabapentin: Continue Urine po 1200 mg po hsfor one week toxicology Continue Observation then titrate down to 0 Pre-& Monitoring days 8-16 (900 mg for 3 treatment MVI/12, Thiamine, days,600 mg for 3 days, Medical Pyridoxine IV 300 mg for 3 days) Assessment150 cc, NTE 150 cc/hr. 1 hour Hydroxyzine 30 mins. Flumazenil 2 mg IVPHCL 50 mg po per administration MVI/12, schedule Thiamine, Pyridoxine IVNTE 150 cc/hr. 30 mins. Flumazenil 2 mg  3 hours MVI/12, Thiamine, IVPper Pyridoxine IV admin. NTE 150 cc/hr. (Total schedule vitamin infusionof 250 cc-500 cc) Continue Observation & Monitoring  3 hours MVI/12,Thiamine, Pyridoxine IV NTE 150 cc/hr. (Total vitamin infusion of 250cc-500 cc) Continue Observation & Monitoring Bedtime Gabapentin BedtimeGabapentin 600 mg po 300 mg po no no later than 21:00 hrs. later thanHydroxyzine HCL 50 mg 21:00 hrs. po @ bedtime may Hydroxyzine repeatwith 25 mg as HCL 50 mg po needed for sleep @ bedtime may repeat with 25mg as needed for sleep

In another exemplary methodology, a patient is treated on an inpatientor outpatient basis for stimulant abuse or on an inpatient or outpatientbasis for stimulant and alcohol abuse.

After a patient has been properly screened and admitted to a treatmentfacility for in-patient treatment, a patient undergoes a first treatmentcycle which comprises a series of treatments over a period of threedays. On the first day, the patient is administered hydroxyzine and aselective chloride channel modulator, preferably flumazenil. In oneembodiment, the patient is administered hydroxyzine HCL 50 mg p.o. onehour before flumazenil infusion. A medical practitioner records the timeof hydroxyzine HCL administration and all subsequent medicationadministrations.

Two infusion bags are prepared. A first infusion bag comprises a 500 ccRingers Lactate Solution to which thiamine and multivitamin componentsare added, and a second infusion bag comprises a 500 cc Ringers LactateSolution for clearing of the line following flumazenil administration.To the first infusion bag is added thiamine 250 mg and a 5 cc MVI vial.An IV is inserted using a stopcock for clearing of the line followingeach dose of flumazenil and subsequent administration of flumazenil. Aheparin-lock may be placed in patients admitted on an in-patient status.The intravenous vitamin infusion is administered at a rate between 200and 250 cc/hour. A medical practitioner preferably obtains and recordsthe patient's pulse, blood pressure and respiratory rate before infusionand every 3-5 minutes following flumazenil administration.

The medical practitioner should use the stopcock, stop the flow ofvitamins and washout out the line going to the patient with the Ringer'sLactate Solution until no further color is seen in the line going to thepatient. Flumazenil should then be administered, as described below,clearing the line with the Ringer's Lactate Solution after each dose offlumazenil.

In a freely flowing intravenous infusion, flumazenil should beadministered via IV over about 1 minute as follows:

-   -   0.1 mg every 3 minutes for two doses.    -   0.2 mg every 3 minutes for two doses.    -   0.3 mg every 2 minutes until the total dose of 2 mg has been        given.

If, when increasing dose or decreasing time between doses, discomfort ofany kind is observed or reported, the drug administration should bereturned to the pre-discomfort level or even returned to initial levels.The standard total dose of flumazenil administration is 6 mg for thefirst treatment cycle and 4 mg for second treatment cycle giving a totaldose of 10 mg.

Once the flumazenil administration is complete, the vitamin infusion cancontinue. The patient is to be medically monitored for three hours postflumazenil administration. During the monitoring process, CIWA-Arassessment should be repeated if treating for combination stimulant andalcohol dependence.

At bedtime, the patient is administered gabapentin 300 mg orally andhydroxyzine HCL at bedtime if a medical practitioner determines apatient needs it for sleep.

On the second day, the patient is administered, as detailed above,hydroxyzine and flumazenil. At bedtime, the patient is administeredgabapentin 600 mg p.o and hydroxyzine HCL 50 mg orally if needed forsleep.

On the third day, the patient is administered, as detailed above,hydroxyzine and flumazenil. The patient is instructed to take 900 mg ofgabapentin at bedtime and hydroxyzine HCL 50 mg orally if needed forsleep. Thereafter, the patient is instructed to take 1200 mg ofgabapentin at bedtime if needed and hydroxyzine HCL 50 mg orally ifneeded for sleep. Before discharge, patients are prescribed thefollowing medication: hydroxyzine HCL (50 mg p.o. hs for one week),gabapentin (beginning the day following the first treatment cycle, 1200mg is to be taken at bedtime for until the next treatment cycle andcontinued at 1200 mg for one week following the second treatment cycleand then tapered to zero), multivitamin (once daily p.o. for one month),and thiamine (250 mg p.o. daily for one month).

After a period of time, preferably between 21 and 28 days, the patientis reassessed in a second treatment cycle. In one embodiment, patientswho cannot engage in treatment a pre-designated period, such as 28 days,the patient will be restarted on the first treatment cycle. Thereassessment is conducted using CIWA-Ar in cases where the patient isbeing treated for a combination of stimulant and alcohol dependence. Ifappropriate, the patient is then instructed to gabapentin 1200 mg perday is continued through this second treatment cycle.

In a case where a patient is being treated on an out-patient basis,after a patient has been properly screened, a patient undergoes a firsttreatment cycle which comprises a series of treatments over a period ofthree days. On the first day, the patient is administered hydroxyzineand a Selective Chloride Channel Modulator, preferably flumazenil. Inone embodiment, the patient is administered hydroxyzine HCL 50 mg p.o.one hour before flumazenil infusion in a manner as described above.After completing the infusion, the patient is administered gabapentin300 mg orally and the CIWA-Ar assessment is repeated if treating for acombination of stimulant and alcohol dependence. The patient may bereleased when the CIWA-AR score is <6. The patient is provided with 50mg hydroxyzine HCL and instructions to take before bedtime if needed forsleep.

On the second day, the patient is administered hydroxyzine and aSelective Chloride Channel Modulator, preferably flumazenil. In oneembodiment, the patient is administered hydroxyzine HCL 50 mg p.o. onehour before flumazenil infusion in a manner as described above. Aftercompleting the infusion, the patient is administered gabapentin 600 mgp.o. and the CIWA-Ar assessment is repeated if treating for acombination of stimulant and alcohol dependence. The patient may bereleased when the CIWA-AR score is <6. The patient is provided with 50mg hydroxyzine HCL and instructions to take before bedtime if needed forsleep.

On the third day, the patient is administered hydroxyzine and aSelective Chloride Channel Modulator, preferably flumazenil. In oneembodiment, the patient is administered hydroxyzine HCL 50 mg p.o. onehour before flumazenil infusion in a manner as described above. Aftercompleting the infusion, the patient is administered gabapentin 900 mgp.o. and the CIWA-Ar assessment is repeated if treating for acombination of stimulant and alcohol dependence. The patient may bereleased when the CIWA-AR score is <6.

At the end of the third day of treatment, patients are prescribed thefollowing medication: hydroxyzine HCL (50 mg p.o. hs for one week),gabapentin (beginning the day following the first treatment cycle, 1200mg is to be taken at bedtime for until the next treatment cycle andcontinued at 1200 mg for one week following the second treatment cycleand then tapered to zero), multivitamin (once daily p.o. for one month),and thiamine (250 mg p.o. daily for one month).

After a period of time, preferably between 21 and 28 days, the patientis reassessed in a second treatment cycle. In one embodiment, patientswho cannot engage in treatment a pre-designated period, such as 28 days,the patient will be restarted on the first treatment cycle. Thereassessment is conducted using CIWA-Ar in cases where the patient isbeing treated for a combination of stimulant and alcohol dependence.

Provided in Tables 8 and 9 below are further details on this specificmethodology example.

TABLE 8 Procedures during Treatment Cycle 1 Post- Day 1 Day 1 Day 2 Day3 Day 3 discharge Time (Admission) Time Day 2 Time (Discharge)medications 30 Negative 30 Negative 30 Negative Hydroxyzine min. Urinemin. Urine min. Urine HCL: 50 mg po toxicology toxicology toxicology hsfor one Pre- (out-patient (out-patient Week treatment only) only)Gabapentin Medical 300 mg day 1, Assessment 600 mg day 2, 1 Hydroxyzine1 Hydroxyzine 1 Hydroxyzine 900 mg day 3, hour HCL 50 mg po hour HCL 50mg po hour HCL 50 mg po 1200 mg days Continue Continue Continue 4-30,900 mg Observation & Observation & Observation & days 31-33, MonitoringMonitoring Monitoring 600 mg days MVI/12, MVI/12, MVI/12, 34-36, andThiamine, Thiamine, Thiamine, 300 mg days IV 200-250 IV 200-250 IV200-250 37-39 cc/hr. cc/hr. cc/hr. Multivitamin 30 Flumazenil 30Flumazenil 30 Flumazenil and Thiamine min. IVP per min. IVP per min. IVPper 100 mg: po admin. administration admin. for one month scheduleschedule schedule (cumulative (cumulative (cumulative dose of 2 mg) doseof 2 mg) dose of 2 mg) 3 Complete 3 Complete 3 Complete hours MVI/12,hours MVI/12, hours MVI/12, Thiamine, IV Thiamine, IV Thiamine, IV 150cc-200 150 cc-200 150 cc-200 cc/hr. cc/hr. cc/hr. Continue ContinueContinue Observation Observation & Observation & & Monitoring MonitoringMonitoring Gabapentin 900 mg po Bed- Gabapentin 300 Bed- Gabapentin 600Discharge time mg po no later time mg po no later w/medication, than21:00 than 21:00 continuing hrs. but after hrs. but after care CIWA-ArCIWA-Ar recommen- assessment assessment dations and HydroxyzineHydroxyzine appointment HCL 50 mg po @ HCL 50 mg po @ for treatmentbedtime may bedtime may cycle 2 repeat with 25 repeat with 25 mg asneeded mg as needed for sleep for sleep

TABLE 9 Procedures during Treatment Cycle 2 Day 1 Day 1 Day 2 Day 2Post-discharge Time (Admission) Time (Discharge) medications 30 NegativeUrine 30 Negative Urine Gabapentin 300 mg min. toxicology min.toxicology day 1, 600 mg Pre-treatment (screen out- day 2, 900 mgMedical patient only) day 3, 1200 mg Assessment days 4-30, 900 1Hydroxyzine HCL 1 Hydroxyzine HCL mg days 31-33, hour 50 mg po hour 50mg po 600 mg days 34- Continue Continue 36, and 300 mg Observation &Observation & days 37-39 Monitoring Monitoring MVI/12, Thiamine, MVI/12,Thiamine, IV 200-260 cc/hr. IV 200-250 cc/hr. 30 Flumazenil IVP 30Flumazenil IVP min. per administration min. per schedule administration(cumulative schedule dose of 2 mg) (cumulative dose of 2 mg) 3 MVI/12,Thiamine, 3 MVI/12, Thiamine, hours IV 200-250 cc/hr. hours IV 200-250cc/hr. Continue Continue Observation & Observation & MonitoringMonitoring Bed- Gabapentin 1200 Discharge w/ time mg po no latermedication than 21:00 hrs. instructions and continuing carerecommendations

In another exemplary methodology, a patient is treated on an inpatientbasis for alcohol abuse. After a patient has been properly screened andadmitted to a treatment facility for in-patient treatment, a patientundergoes a first treatment cycle, which comprises a series oftreatments over a period of two to three days. Preferably the intervalbetween treatment episodes should be no less than 12 hours and nogreater than 30 hours.

On the first day, the patient is administered hydroxyzine and aSelective Chloride Channel Modulator, preferably flumazenil. In oneembodiment, the patient is administered hydroxyzine HCL 50 mg p.o. onehour before flumazenil infusion. A medical practitioner records the timeof hydroxyzine HCL administration and all subsequent medicationadministrations.

Two infusion bags are prepared. A first infusion bag comprises a 500 ccRingers Lactate Solution to which thiamine and multivitamin componentsare added, and a second infusion bag comprises a 500 cc Ringers LactateSolution for clearing of the line following flumazenil administration.To the first infusion bag is added thiamine 100 mg and a 5 cc MVI vial.An IV is inserted using a stopcock for clearing of the line followingeach dose of flumazenil and subsequent administration of flumazenil. Aheparin-lock may be placed in patients admitted on an in-patient status.The intravenous vitamin infusion is administered at a rate between 150and 200 cc/hour. A medical practitioner preferably obtains and recordsthe patient's pulse, blood pressure and respiratory rate before infusionand every 3-minutes following flumazenil administration.

The medical practitioner should use the stopcock, stop the flow ofvitamins and washout out the line going to the patient with the Ringer'sLactate Solution until no further color is seen in the line going to thepatient. Flumazenil should then be administered, as described below,clearing the line with the Ringer's Lactate Solution after each dose offlumazenil.

In a freely flowing intravenous infusion, flumazenil should beadministered via IV over about 1 minute as follows:

-   -   0.1 mg every 3 minutes for two doses.    -   0.2 mg every 3 minutes for two doses.    -   0.3 mg every 2 minutes until the total dose of 2 mg has been        given.

If, when increasing dose or decreasing time between doses, discomfort ofany kind is observed or reported, the drug administration should bereturned to the pre-discomfort level or even returned to initial levels.The standard total dose of flumazenil administration is 4 mg for twotreatment episodes (treatment days one and two) and 6 mg for threetreatment episodes (treatment days one, two and three).

Once the flumazenil administration is complete, the vitamin infusion cancontinue. The patient is to be medically monitored for three hours postflumazenil administration. During the monitoring process, CIWA-Arassessment should be repeated.

At bedtime, such as around 9 p.m., the patient is administeredgabapentin 300 mg p.o. and 50 mg p.o. hs of hydroxyzine HCL. The patientis also assessed with the CIWA-Ar.

On the second day, the patient is administered, as detailed above,hydroxyzine and flumazenil. The patient is administered gabapentin 600mg p.o prior to discharge and 50 mg p.o. hs hydroxyzine HCL. Dependingon a patients'CIWA-Ar score, some patients may need a third day oftreatment. If a third treatment episode, i.e. a third day, is required,the patient is administered 600 mg p.o. gabapentin prior to 9 p.m. and900 mg gabapentin p.o. prior to discharge.

At the end of the final day of treatment, patients are prescribed thefollowing medication: hydroxyzine HCL (50 mg p.o. hs for one week),gabapentin (beginning the day following the first treatment cycle, 900mg p.o. hs for 30 days, 600 mg p.o. hs for days 31-33, and 300 mg p.o.hs for days 34-37), multivitamin (once daily p.o. for one month), andthiamine (100 mg p.o. daily for one month).

TABLE 10 Treatment for Alcohol Dependence Administration during 2 dayin-patient stay Day 1 Day 1 Day 2 Day 2 Post-discharge Time (AdmissionDay) Time (Discharge) Medications 30 min. Negative Urine  1 hourHydroxyzine HCL Hydroxyzine HCL: toxicology. 50 mg po 50 mg po hs forPre-treatment Continue One week Medical Assessment Observation &Gabapentin: Monitoring Begin day MVI/12, Thiamine, following IVdischarge 900 mg 125 cc-150 cc/hr po hs for 30  1 hour Hydroxyzine HCL30 min. Flumazenil 2 mg IVP days then 50 mg po per administrationtitrate down to MVI/12, Thiamine, schedule 0 days 31-37 IV (600 mg for 3125 cc-150 cc/hr. days, 300 mg for 30 min. Flumazenil 2 mg IVP  3 hoursMVI/12, Thiamine, 3 days) per administration IV Multivitamin andschedule 125 cc-150 cc/hr. Thiamine 100 mg: (Total vitamin po for Onemonth infusion of 250 cc-500 cc) Continue Observation & MonitoringGabapentin 600 mg po  3 hours MVI/12, Thiamine IV May discharge if 125cc-150 cc/hr. CIWA-AR <6 (Total vitamin Discharge w/ infusion of 250cc-500 cc) medication Continue instructions and Observation & continuingcare Monitoring recommendations Bed- Gabapentin 300 mg If day 3 needed:time po no later than See Table 11 21:00 hrs. but after CIWA-Arassessment Hydroxyzine HCL 50 mg po @ bedtime may repeat with 25 mg asneeded for sleep

TABLE 11 Treatment for Alcohol Dependence During 3 day in- patient stay(Day 3 required if CIWA ≧10 on day 1 or day 2 or CIWA >6 post infusionon day 2) Post- Day 1 Day 1 Day 2 Day 3 Day 3 discharge Time (Admission)Time Day 2 Time (Discharge) medications 30 min. Negative  1 hourHydroxyzine  1 hour Hydroxyzine Hydroxyzine Urine HCL 50 mg po HCL 50 mgpo HCL: 50 mg toxicology Continue Continue po hs for Pre- Observation &Observation & One Week treatment Monitoring Monitoring Gabapentin:Medical MVI/12, MVI/12, Begin day Assessment Thiamine, IV Thiamine, IVfollowing 125 cc-150 cc/hr. 125 cc-150 cc/hr. discharge  1 hourHydroxyzine 30 min. Flumazenil 2 mg 30 min. Flumazenil 2 mg 900 mg poHCL 50 mg po IVP IVP hs for 30 MVI/12, per per admin. days thenThiamine, IV administration schedule taper days 125-150 cc/hr. schedule31-37 (600 mg 30 min. Flumazenil 2 mg  3 hours MVI/12,  3 hours MVI/12,for 3 IVP per Thiamine, IV Thiamine, IV days, 300 mg admin. 125 cc-150cc/hr. 125 cc-150 cc/hr. for 3 schedule (Total (Total days) vitaminvitamin Multivitamin infusion of infusion of and 250 cc-500 cc) 250cc-500 cc) Thiamine Continue Continue 100 mg: po Observation &Observation & for One Monitoring Monitoring Month Gabapentin 900 mg po 3 hours MVI/12, Discharge w/ Thiamine, medication IV 125 cc-150 cc/hr.instructions Continue and Observation continuing & Monitoring carerecommendations Bed- Gabapentin Bed- Gabapentin 600 mg time 300 mg po notime po no later later than than 21:00 hrs. 21:00 hrs. but after butafter CIWA-Ar CIWA-Ar assessment assessment Hydroxyzine Hydroxyzine HCL50 mg po @ HCL 50 mg po bedtime may @ bedtime repeat with 25 mg mayrepeat as needed with 25 mg for sleep as needed for sleep

In another exemplary methodology, a patient is treated on an outpatientbasis for alcohol abuse. After a patient has been properly screened, apatient undergoes a first treatment cycle, which comprises a series oftreatments over a period of two days. Preferably the interval betweentreatment episodes should be no less than 12 hours and no greater than30 hours.

On the first day, the patient is administered hydroxyzine and aSelective Chloride Channel Modulator, preferably flumazenil. In oneembodiment, the patient is administered hydroxyzine HCL 50 mg p.o. onehour before flumazenil infusion. A medical practitioner records the timeof hydroxyzine HCL administration and all subsequent medicationadministrations.

Two infusion bags are prepared. A first infusion bag comprises a 500 ccRingers Lactate Solution to which thiamine and multivitamin componentsare added, and a second infusion bag comprises a 500 cc Ringers LactateSolution for clearing of the line following flumazenil administration.To the first infusion bag is added thiamine 100 mg and a 5 cc MVI vial.An IV is inserted using a stopcock for clearing of the line followingeach dose of flumazenil and subsequent administration of flumazenil. Aheparin-lock may be placed in patients admitted on an in-patient status.The intravenous vitamin infusion is administered at a rate between 150and 200 cc/hour. A medical practitioner preferably obtains and recordsthe patient's pulse, blood pressure and respiratory rate before infusionand every 3-5 minutes following flumazenil administration.

The medical practitioner should use the stopcock, stop the flow ofvitamins and washout out the line going to the patient with the Ringer'sLactate Solution until no further color is seen in the line going to thepatient. Flumazenil should then be administered, as described below,clearing the line with the Ringer's Lactate Solution after each dose offlumazenil.

In a freely flowing intravenous infusion, flumazenil should beadministered via IV over about 1 minute as follows:

-   -   0.1 mg every 3 minutes for two doses.    -   0.2 mg every 3 minutes for two doses.    -   0.3 mg every 2 minutes until the total dose of 2 mg has been        given.

If, when increasing dose or decreasing time between doses, discomfort ofany kind is observed or reported, the drug administration should bereturned to the pre-discomfort level or even returned to initial levels.The standard total dose of flumazenil administration is 4 mg for twotreatment episodes (treatment days one and two).

Once the flumazenil administration is complete, the vitamin infusion cancontinue. The patient is to be medically monitored for three hours postflumazenil administration. During the monitoring process, CIWA-Arassessment should be repeated.

Prior to releasing the patient after treatment cycle one, the patientassessed with the CIWA-Ar and released if the score is less than 6. Thepatient is administered gabapentin 300 mg p.o. The patient is alsoinstructed to take 50 mg p.o. hs of hydroxyzine HCL before bedtime.

On the second day, the patient is administered, as detailed above,hydroxyzine and flumazenil. The patient is assessed using CIWA-Ar andadministered gabapentin 600 mg p.o prior to discharge.

At the end of the final day of treatment, patients are prescribed thefollowing medication: hydroxyzine HCL (50 mg p.o. hs for one week),gabapentin (beginning the day following the first treatment cycle, 900mg p.o. hs for 30 days, 600 mg p.o. hs for days 31-33, and 300 mg p.o.hs for days 34-37), multivitamin (once daily p.o. for one month), andthiamine (100 mg p.o. daily for one month).

TABLE 13 Treatment for Alcohol Dependence Administration during 2 dayout-patient treatment Day 1 Day 2 Final Discharge Time Day 1 Time Day 2Medications 30 min. Negative Urine 30 min. Negative Urine HydroxyzineHCL: toxicology toxicology 50 mg po hs for Pre-treatment one weekMedical Assessment Gabapentin:  1 hour Hydroxyzine HCL  1 hourHydroxyzine HCL Begin day 50 mg po 50 mg po following Continue Continuedischarge 900 mg Observation & Observation & po hs for 30 MonitoringMonitoring days then taper MVI/12, Thiamine, MVI/12, Thiamine, to 0 days31-37 IV IV (600 mg for 3 125 cc-150 cc/hr. 150 cc-200 cc/hr days, 300mg for 30 min. Flumazenil IVP per 30 min. Flumazenil IVP 3 days)administration per administration Multivitamin and schedule scheduleThiamine 100 mg: (cumulative dose of (cumulative dose of po for Onemonth 2 mg) 2 mg)  3 hours Complete MVI/12,  3 hours Complete MVI/12,Thiamine IV 150 cc-200 cc/hr. Thiamine, IV Continue 150 cc-200 cc/hr.Observation & Continue Monitoring Observation & Gabapentin 300 mgMonitoring po Gabapentin 600 mg po Release May discharge if Maydischarge if to CIWA-AR <6 CIWA-AR <6 accompanying Discharge w/Discharge w/ person medication medication instructions and instructionsand scheduled time for continuing care day 2 treatment recommendationsBedtime Hydroxyzine HCL 50 mg po @ bedtime may repeat with 25 mg asneeded for sleep

In another exemplary methodology, a patient is treated for alcoholdependence. Preferably, in this treatment methodology, the intervalbetween treatment episodes, implemented in a series, should be no lessthan 12 hours and no greater the 24 hours.

On day one, the patient is administered 50 mg of hydroxyzine HCL 50p.o., unless otherwise contraindicated. After at least one-hour, theSelective Chloride Channel Modulator, such as flumazenil, isadministered. Prior to Selective Chloride Channel Modulator infusion,two infusion bags are prepared. The first infusion bag comprises 500 cc½ normal saline (NS) to which thiamine, pyridoxine and other vitamincomponents are added and the second infusion bag comprises 500 cc ½ NSfor clearing the line and for subsequent Selective Chloride ChannelModulator administration. 100 mg of thiamine, 25 mg of pyridoxine, and 5cc of MVI is preferably added to the first infusion bag. The firstinfusion bag is administered to the patient at 125 cc/hr (NTE 150cc/hour) by placing the IV in the antecubital fossa. The IV line shouldfurther include the use of a stopcock for clearing of the line andsubsequent administration of the Selective Chloride Channel Modulator.Using the stopcock, the line should be washed out with the ½ NS until nofurther color is seen in the line going to the patient.

Once the line is washed, the Selective Chloride Channel Modulatoradministration can be initiated. Where the Selective Chloride ChannelModulator is flumazenil, a total dose of 2 mg is given at each treatmentepisode. The medication should be given by IV bolus as follows: a) 0.1mg every 3 minutes for two doses, b) 0.2 mg every 3 minutes for twodoses; and c) 0.3 mg every 2 minutes until the total dose of 2 mg hasbeen given. If, when increasing dose or decreasing time between doses,discomfort of any kind is observed or reported, the drug administrationshould be returned to the pre-discomfort level or even returned toinitial levels. In one embodiment, the total dose of flumazeniladministration is 6 mg for the first treatment cycle (three treatmentepisodes) and 4 mg for the second treatment cycle (two treatmentepisodes). Parameters of flumazenil administration could be modified insome cases. Quantities can be higher than the 2 mg dose or can be higherthan 0.3 mg per administration. Additionally, time periods betweenadministrations can be increased or decreased slightly. Once theflumazenil administration is complete, the vitamin infusion can bereinitiated once the line is cleared with ½ NS. The patient should bemonitored for 3 hours post flumazenil administration during which timerepeat CIWA-Ar assessments should be performed.

Provided in Tables 7 and 8 below are further details on this specificmethodology example.

In another embodiment of the present invention, a methodology isprovided for the use and administration of a Selective Chloride ChannelModulator, such as flumazenil, for the treatment of cravings for alcoholand stimulants. If administered in accordance with the generalmethodology described above, a therapeutically effective amount of thecompound is maintained in the patient, thereby significantly reducingcravings for alcohol and stimulants. The invention also provides for theadministration of flumazenil without significant side effects.

In another embodiment of the present invention a methodology is providedthat relates to the use and administration of a therapeuticallyeffective quantity of a Selective Chloride Channel Modulator, such asflumazenil, for the treatment of cravings of psychostimulants, reducingwithdrawal symptoms during detoxification and treating addiction ofpsychostimulants and with improvement of cognitive ability, mentalclarity, and focus. If administered in accordance with the methodologyof the present invention, a therapeutically effective amount of the drugis maintained in the patient thereby significantly reducing cravings forpsychostimulants.

The invention also provides for the administration of a SelectiveChloride Channel Modulator so as to reduce, and in some cases, eliminatewithdrawal symptoms and to generally treat addiction topsychostimulants. Preferably, a drug in the class of Selective ChlorideChannel Modulator, such as flumazenil, is administered in multipledosages for a predetermined time period until a therapeuticallyeffective quantity is administered for the reduction of cravings forpsychostimulants.

In another embodiment of the present invention a methodology isdescribed for the use and administration of a therapeutically effectivequantity of a Selective Chloride Channel Modulator, such as flumazenil,for the reduction in patient dropout rates both during theadministration of the treatment and after the treatment. Whenadministered in accordance with the methodology of the presentinvention, a therapeutically effective amount of the compound ismaintained in the patient, thereby significantly reducing cravings foralcohol and certain stimulants, resulting in lower patient dropoutrates. Such dosing also provides for administration of flumazenil withfewer side effects. At these low dosage levels, the treatment is stilleffective for reducing patient dropout rates while also beingtherapeutically effective.

The following examples demonstrate the invention and must not beconsidered to limit the scope thereof.

Example 1 Treatment of Patients With Flumazenil in Multiple Dosages atPredetermined Time Periods 1.1 Experimental Protocol

64 alcoholics (51 males and 13 females) voluntarily entered a treatmentprogram to discontinue the use of alcohol. The patients were providedthe appropriate information and the corresponding informed consent formwas obtained from them. The patients were warned not to drink alcoholthe morning on which the treatment was to be carried out to enablebetter evaluation of the withdrawal symptoms. Table 14 summarizes thecharacteristics of the patients treated associated with alcohol use.

TABLE 14 Characteristics of Patients Associated with Alcohol Use (note:85% consumed alcohol daily and 39.1% consumed benzodiazepines daily).STANDARD CHARACTERISTICS MEAN DEVIATION MINIMUM  MAXIMUM AGE (YEARS)42.7 10.2 20 75 AGE AT BEGINNING 24.6 10.2 6 71 OF DAILY ALCOHOL USE(YEARS) DAILY UNITS OF 24.9 15.4 4 73 ALCOHOL INTAKE GAMMA-GLUTAMYL159.1 227.2 12 1.230 TRANSPEPTIDASE (GGT) CORPUSCULAR 97.8 6.4 72 111VOLUME (RBC) NUMBER OF 1.6 1.2 0 5 PREVIOUS DETOXIFICATIONS

Before starting the treatment, the patients underwent a complete medicaland psychological examination. The monitoring of the patients throughoutthe morning included a complete blood count, a biochemical profile[creatinine, glucose, blood urea nitrogen (BUN), cholesterol (HDL andLDL), triglycerides, alkaline phosphatase, LDH (lactic dehydrogenase)and total proteins], hepatic function tests [GOT, GPT, GGT, bilirubin),electrocardiogram and, if need be, pregnancy test and x-ray examination.The exclusion criteria applied included acute or uncompensatedillnesses, as well as the taking of any drug contraindicated withflumazenil. No patient was excluded after the pre-admission interviewand the tests performed. Admission of one patient was postponed untilhis cardiac pathology was checked.

Before and after the administration of flumazenil, the withdrawalsymptomatology was measured using the CIWA-A evaluation (Adinoff et al.,Medical Toxicology 3:172-196 (1988)), as well as heart rate and bloodpressure. Table 15 presents the treatment protocol followed duringhospitalization.

TABLE 15 Treatment Protocol Followed During Hospitalization. TIME DAY OFADMISSION DAY 2 DAY 3 (DISCHARGE) 9:00 a.m. Clomethiazole 192 mgClomethiazole 192 mg Vitamin B Complex Vitamin B Complex Piracetam 3 g(oral) Piracetam 3 g (oral) Drink with vitamins, Drink with vitamins,minerals, proteins, and minerals, proteins, amino acids and amino acids11:00 a.m.  Flumazenil 2 mg per day 1:00 p.m. Clomethiazole 192 mgVitamin B Complex Piracetam 3 g (oral) 4:30 p.m. Flumazenil 2 mg per day7:30 p.m. Vitamin B Vitamin B Complex Complex Disulfiram 250 mg 9:30p.m. Clomethiazole Clomethiazole 384 mg 384 mg

Flumazenil was administered at a dose of 0.2 mg every 3 minutes (up to atotal of 2 mg/day). This quantity per dose was established to minimizethe adverse side effects associated with withdrawal or interactions withother pharmaceuticals or psychopathologies.

Patients who presented marked anxiety were administered an additionaldose of 192 mg of clomethiazole 30 minutes before administration offlumazenil.

Before discharge from the hospital, the following medications wereprescribed:

-   -   Vitamin B complex: 1 month with one dose during breakfast and        one dose during lunch.    -   Piracetam, or a medicament that is pharmacologically equivalent,        3 g for 1 week with one dose during breakfast and 800 mg for 1        month with one dose during breakfast and one dose during lunch;    -   Fluoxetine 20 mg for 2 months with one dose during breakfast;    -   Clomethiazole 192 mg for 1 week with one dose during breakfast        and one dose during dinner and a subsequent elimination of dose        during the second week;    -   Disulfuram 250 mg with one dose during breakfast.

As part of the treatment program, the patients were instructed to attendthe outpatient treatment center for 9 months with decreasing frequency[once a week for the first three months, once every two weeks during thesecond three months, and once a month during the third three months].

Likewise, a semi-structured follow-up of cognitive behavior therapy wasimplemented. Individual and family psychotherapy was focused on 4 majorinterventions (cognitive restructuring, work therapy, prevention ofrelapse, and stress reduction) aimed at rehabilitating the social,family, work, personal and leisure life of the patient.

1.2 Results

Of the 64 patients treated, in 3 cases, the first administration offlumazenil was interrupted and postponed to the following day: one ofthem, who was obviously intoxicated with alcohol, demonstrated adistressing increase in confusion, another had a significant increase indistal tremors, and the other, who was also addicted to benzodiazepines,demonstrated a significant increase in anxiety. Another group of 3patients received the first dose of flumazenil under sedation withpropofol in the intensive care unit.

Approximately 10% of the patients suffered headache during orimmediately following the administration of flumazenil, whichdisappeared after a few minutes, or after administration of metamizolemagnesium.

1.3 Results after the First Administration of Flumazenil

The CIWA-A scoring of 55 patients showed that: 47.3% had a significantreduction (t: −7.713; p<0.000); 40.0% experienced no change; and 12.7%had a significant increase (t: 2.511; p<0.046) [in the three casespresenting the greatest increase, the treatment was discontinued].

The heart rate values of 55 patients showed that: 50.9% had asignificant reduction (t: −8.820; p<0.000); 40.0% experienced no change;and 9.1% had a significant increase (t: 4.750; p<0.009).

The systolic blood pressure values of 53 patients showed that: 47.2% hada significant reduction (t: −9.908; p<0.000); 37.7% experienced nochange; and 15.1% had a significant increase (t: 4.314; p<0.004).

The diastolic blood pressure values of 53 patients showed that: 34% hada significant reduction (t: −9.220; p<0.000); 47.2% experienced nochange; and 18.9% had a significant increase (t: 5.511; p<0.000).

1.4 Results After the Second Administration of Flumazenil

The CIWA-A scoring of 58 patients showed that: 36.2% had a significantreduction (t: −5.363; p<0.000); 55.2% experienced no change; and 8.6%had a significant increase (t: 4.000; p<0.016).

The heart rate values of 55 patients showed that: 41.8% had asignificant reduction (t: −8.523; p<0.000); and 58.2% experienced nochange.

The systolic blood pressure values of 56 patients showed that: 28.6 hada significant reduction (t: −7.596; p<0.000); 55.4% experienced nochange; and 16.1% had a significant increase (t: 4.612; p<0.002).

The diastolic blood pressure values of 56 patients showed that: 28.6%had a significant reduction (t: −6.325; p<0.000); 51.8% experienced nochange (n=29); and 19.6% had a significant increase (t: 6.640; p<0.000).

Table 16 statistically summarizes the results obtained before and afterthe treatment (at the end of 18 hours). Table 17 summarizes thefollow-up data.

TABLE 16 Statistical Summary of Results Obtained Before and AfterTreatment Standard No. of Deviation Mean Student's Mean (M) Samples (SD)Error T Factor Significance BT* AT** BT AT BT AT BT AT BT AT BT ATCIWA-A 4.13 .76 54 54 4.28 1.52 0.58 0.21 6.19 .002 Systolic 135.2126.67 51 51 18.22 13.99 2.55 1.96 5.256 0.0 Blood Pressure Diastolic86.27 82.75 51 51 10.76 9.13 1.51 1.28 3.273 .002 Blood Pressure Heart81.42 75.02 53 53 13.83 9.93 1.9 1.36 4.273 0.0 Rate *Before Treatment,**After Treatment

TABLE 17 Summary of Follow-Up Data TIME Month 1 Month 3 Month 6 Month 9(% N) 67.2/43 34.4/22 18.8/12 12.5/8 Therapy and 95.3%  86.4%  75%   75%Disulfiram Therapy without 4.5% 12.5% Disulfiram Dropouts 4.7% 9.1% 25%12.5%

The psychophysiological functions such as appetite and sleep wereregained very rapidly during hospitalization. The second day ofhospitalization, the patients were permitted to spend a few hoursoutside the clinic during the afternoon. Some patients had dinneroutside the clinic. The most striking result is the spontaneous verbalreport from the majority of the patients concerning the absence ofanxiety and of the desire to drink alcohol.

Example 2 Improved Methodology for the Administration of Flumazenil toTreat Alcohol Dependency

Before starting the protocol, the patients underwent a complete medicaland psychological examination. The monitoring of the patients included acomplete blood count, a biochemical profile [creatinine, glucose, bloodurea nitrogen (BUN), cholesterol (HDL and LDL), triglycerides, alkalinephosphatase, LDH (lactic dehydrogenase) and total proteins], hepaticfunction tests [GOT, GPT, GGT, bilirubin), electrocardiogram and, ifneed be, pregnancy test and x-ray examination. The exclusion criteriaapplied included acute or uncompensated illnesses, as well as the takingof any drug contraindicated with flumazenil. No patient was excludedafter the pre-admission interview and the tests performed.

In addition, patients diagnosed with a psychotic disorder receivedanti-psychotic medication. Patients diagnosed with arterial hypertensionare prescribed the appropriate medication or instructed to continue withany existing medication.

Patients were then intravenously administered 0.1 mg of flumazenil every3 minutes for two administrations. If the patient did not experience anydiscomfort, then the dosage was increased up to 0.3 mg every 2 minutes.The total dosage of flumazenil administered was up to 3.0 mg per day foralcohol dependency over the course of the treatment.

Patients were also administered amino acids, nutrients, and vitamins.Non-addictive sedatives were also administered in order to reducepatient stress and/or discomfort.

Following administration of the protocol, patients underwent 6 to 24months of outpatient therapy (for the first two months, once a week; thenext four months, every two weeks; the next six months, once a month;and the last twelve months, once every two months). Depending on thepatient, the outpatient treatment included cognitive behavioralsemi-structured follow-up, such as individual and family psychotherapythat may include cognitive restructuring, network therapy, relapseprevention and stress reduction.

Example 3 Improved Methodology for the Administration of Flumazenil toTreat Alcohol Dependency

In accordance with this embodiment of the present invention, as relatedto such example, a protocol for the treatment of alcohol cravings isdescribed in the table below:

Time Day 3 - Admission Day Day 2 Discharge Pre-Procedure Atarax AtaraxFortified (AM) (sedative) - (sedative) - Vitamin B 50 mg (1-2 hour 50 mg(1-2 hour complex. pre-procedure). pre-procedure). Protein May repeatwith May repeat with Drink. 25 mg for 25 mg for anxiety if anxiety ifneeded. needed. Fortified Fortified Vitamin B Vitamin B complex.complex. Protein Drink. Protein Drink. Procedure Flumazenil 2 mgFlumazenil 2 mg per day per day Post-Procedure Atarax 50 mg. at Atarax50 mg. at (PM) bedtime may bedtime may repeat with 25 mg. repeat with 25mg. as needed as needed for sleep. for sleep.At discharge, the following may be administered: disulfuram 250 mg.,daily for six months; glutamic acid, 500 mg., once daily for one day,twice daily for one day, then three times daily for two weeks; vitamin Bcomplex daily; and Atarax, 50 mg. at bedtime for one week and then 25mg. at bedtime for a week.

Example 4 Improved Methodology for the Administration of Flumazenil toTreat Cocaine Dependency

Before starting the protocol, the patients underwent a complete medicaland psychological examination. The monitoring of the patients included acomplete blood count, a biochemical profile [creatinine, glucose, urea,cholesterol (HDL and LDL), triglycerides, alkaline phosphatase, LDH(lactic dehydrogenase) and total proteins], hepatic function tests [GOT,GPT, GGT, bilirubin), electrocardiogram and, if warranted, pregnancytest and x-ray examination. The exclusion criteria applied includedacute or uncompensated illnesses, as well as the taking of any drugcontraindicated with flumazenil. No patient was excluded after thepre-admission interview and the tests performed.

In addition, patients diagnosed with a psychotic disorder receivedanti-psychotic medication. Patients diagnosed with arterial hypertensionwere prescribed with the appropriate medication or instructed tocontinue with any existing medication.

Patients were administered 0.1 mg of flumazenil every 3 minutes for twoadministrations. If the patient did not experience any discomfort, thedosage was increased up to 0.3 mg every 2 minutes. The total dosage offlumazenil administered was up to 3 mg per day over the course of thetreatment.

Patients were also selectively administered amino acids, nutrients, andvitamins. Non-addictive sedatives were also administered in order toreduce patient stress and/or discomfort. Following administration of theprotocol, patients underwent 6 to 24 months of outpatient therapy (forthe first two months, once a week; the next four months, every twoweeks; the next six months, once a month; and the last twelve months,once every two months). Depending on the patient, the outpatienttreatment included cognitive behavioral semi-structured follow, such asindividual and family psychotherapy that may include cognitiverestructuring, network therapy, relapse prevention and stress reduction.

Example 5 Improved Methodology for the Administration of Flumazenil toTreat Cocaine Dependency

In accordance with this embodiment of the present invention, as relatedto such example, a protocol for the treatment of cravings for cocaine isdescribed in the table below:

Day 3 - Time Admission Day Day 2 Discharge Pre-Procedure Atarax AtaraxFortified (AM) (sedative) - (sedative) - Vitamin B 50 mg (1-2 hour 50 mg(1-2 hour complex. pre-procedure). pre-procedure). Protein May repeatwith May repeat with Drink. 25 mg for 25 mg for anxiety if anxiety ifneeded. needed. Fortified Fortified Vitamin B Vitamin B complex.complex. Protein Drink. Protein Drink. Procedure Flumazenil 2 mgFlumazenil 2 mg per day per day Post-Procedure Atarax 50 mg. at Atarax50 mg. at (PM) bedtime may bedtime may repeat with 25 mg. repeat with 25mg. as needed as needed for sleep. for sleep.

At discharge, the following may be administered: Neurontin 400 mg. dailyfor one day (at morning), then two times daily for one day (morning andbedtime), then three times daily and continuing for six months (decreaseby 400 mg. weekly in order to discontinue); glutamic acid, 500 mg., oncedaily for one day, twice daily for one day, then three times daily fortwo weeks; vitamin B complex daily; and Atarax, 50 mg. at bedtime forone week and then 25 mg. at bedtime for a week.

Example 6 Enhanced Methodology for the Administration of Flumazenil forthe Treatment of Alcohol Withdrawal

The following example is of an embodiment of an enhanced protocol forthe administration of flumazenil for the treatment of alcoholdependency. The enhanced protocol is implemented to concentratetargeting of GABA_(A) Receptor Ionophore Complex. The embodiment employsa CIWA-based algorithm for 1) triage of patients in need of acutemedical detoxification and 2) to provide symptom-based trackingthroughout acute phase of the protocol treatment. The enhanced protocolalso alleviates withdrawal related sleep disturbance and anxiety. Inaddition, the enhanced protocol supplies key co-factors thatsynergistically enhance GABA tone and transmission.

In the exemplary enhanced protocol for treating alcohol withdrawal, apatient undergoes the aforementioned pre-treatment regimen. On day 1 oftreatment, the patient receives flumazenil via an intravenous infusion,ultimately delivering a total amount of 2 mg per dosing interval. Thepatient further receives 50 mg of hydroxyzine during the day and 50 mgof hydroxyzine at bedtime or in the evening. The patient furtherreceives fortified vitamin B complex and Gabapentin at a dose of 300 mg.

On day 2 of treatment, the patient receives flumazenil via anintravenous infusion, ultimately delivering a total amount of 2 mg perdosing interval. The patient further receives 50 mg of hydroxyzineduring the day and 50 mg of hydroxyzine at bed or in the evening. Thepatient further receives fortified vitamin B complex daily andGabapentin at a dose of 300 mg in the afternoon and evening or atbedtime.

After discharge, for days one and two, the patient receives 50 mg ofhydroxzine at bedtime or in the evening. For 30 days, the patientreceives Gabapentin at a dose of 900 mg in the afternoon and evening orat bedtime then titrating down to 0. For one week, the patient alsoreceives vitamin B complex daily.

Example 7 Enhanced Methodology for the Administration of Flumazenil forthe Treatment of Alcohol Withdrawal

In a third exemplary methodology for treating alcohol withdrawal, apatient undergoes a pre-treatment procedure that includes a CIWAassessment and the administration of hydroxyzine at a dose of 50 mg. Onday one of treatment, a first infusion is administered to the patient.The first infusion includes vitamin B1, vitamin B6, vitamin B12, andvitamin B complex and 2 mg of flumazenil over a period of 2 hours. Afterthe first infusion, the patient undergoes a post-treatment procedure,typically in the late afternoon to evening that includes a CIWAassessment, the administration of Gabapentin at a dose of 300 mg, andthe administration of hydroxyzine at a dose of 50 mg in the evening orbedtime.

On day two of treatment, a patient undergoes a pre-treatment procedurethat includes a CIWA assessment and the administration of hydroxyzine ata dose of 50 mg. A second infusion is then administered to the patient.The second infusion includes vitamin B1, vitamin B6, vitamin B12, andvitamin B complex and 2 mg of flumazenil over a period of 2 hours. Afterthe second infusion, the patient undergoes a post-treatment procedure,typically in the late afternoon to evening that includes a CIWAassessment, the administration of Gabapentin at a dose of 300 mg, andthe administration of hydroxyzine at a dose of 50 mg in the evening orbedtime.

After discharge, the patient is monitored based on the CIWA assessmentand the patient's medical condition. Optionally, prior to discharge, thepatient undergoes a third day of treatment that is similar to day 2, ifwarranted by the patient's medical condition and/or CIWA assessment.

At discharge, the patient is given 50 mg of hydroxyzine on days 1 and 2at bedtime. The patient is also given gabapentin in the followingamounts: 300 mg on day 1; 600 mg on day 2; and on days 3-30, 900 mgtitrated down to zero. The patient is also given an Oral Vitamin B 100complex daily for one week.

Example 8 Enhanced Methodology for the Administration of Flumazenil forthe Treatment of Stimulant Withdrawal

The following example is of an embodiment of an enhanced methodology forthe administration of flumazenil for the treatment of psychostimulantdependency. The enhanced methodology is implemented to concentratetargeting of GABA_(A) Receptor Ionophore Complex. The embodiment allowsfor streamlining of nutritional components. In addition, the enhancedmethodology also alleviates withdrawal related sleep disturbance andanxiety. The enhanced methodology also supplies key co-factors thatsynergistically enhance GABA tone and transmission.

In a first exemplary enhanced methodology for treating stimulantwithdrawal, a patient undergoes the aforementioned pre-treatmentregimen. On days 1, 2 and 3 of treatment, the patient receivesflumazenil via an intravenous infusion, ultimately delivering a totalamount of 2 mg per dosing interval. The patient further receives 50 mgof hydroxyzine twice daily plus or minus 25 mg as may be required. Thepatient further receives fortified vitamin B complex daily and a proteinsupplement drink daily in the morning. This regimen, preferably days 1and 2 only, is repeated after three weeks.

After discharge, for one week, the patient receives 50 mg of hydroxyzineat bedtime or for sleep and, for a subsequent week, the patient receives25 mg of hydroxyzine at bedtime or for sleep. For two weeks, the patientalso receives glutamine titrated up to 1500 mg per day and fortifiedvitamin B complex daily. The patient further receives Gabapentintitrated up to 1200 mg per day for six months. This regimen isinterrupted for a second round of treatments, as described above, afterthree weeks have elapsed from the first round of treatments andrestarted thereafter.

Example 9 Enhanced Methodology for the Administration of Flumazenil forthe Treatment of Stimulant Withdrawal

In a second exemplary methodology for treating stimulant withdrawal, apatient undergoes the aforementioned pre-treatment regimen. On days 1, 2and 3 of treatment, the patient receives flumazenil via an intravenousinfusion, ultimately delivering a total amount of 2 mg per dosinginterval. The patient further receives 50 mg of hydroxyzine. The patientfurther receives fortified vitamin B complex daily and Gabapentin at adose of 300 mg. This regimen, preferably days 1 and 2 only, is repeatedafter three weeks.

After discharge, the patient receives Gabapentin titrated up to 400 mgper day for 30 days, decreasing to 0. The patient also receivesfortified vitamin B 100 complex daily and a plurality of amino acidsupplements. This regimen is interrupted for a second round oftreatments, as described above, after three weeks have elapsed from thefirst round of treatments and restarted thereafter.

The above examples are merely illustrative of the many applications ofthe system of present invention. Although only a few embodiments of thepresent invention have been described herein, it should be understoodthat the present invention might be embodied in many other specificforms without departing from the spirit or scope of the invention.Therefore, the present examples and embodiments are to be considered asillustrative and not restrictive, and the invention is not to be limitedto the details given herein, but may be modified within the scope of theappended claims.

1-29. (canceled)
 30. A method for the treatment of alcohol abuse in apatient comprising the steps of: evaluating the patient; administering atherapeutically effective amount of a composition comprising a selectivechloride channel modulator in a pharmaceutically acceptable carrier tothe patient; monitoring the patient during treatment; prescribing thepatient a therapeutic compound in addition to the selective chloridechannel modulator; and prescribing the patient an outpatient regimen.31. The method of claim 30 wherein the patient evaluation step comprisesat least one of the following: a complete physical examination, acomplete psychological examination, a CIWA assessment, and adetermination of required medications.
 32. The method of claim 30wherein the selective chloride channel modulator is flumazenil.
 33. Themethod of claim 32 wherein the therapeutically effective amount offlumazenil is between about 1.0 and 3.0 mg/day.
 34. The method of claim32 wherein the therapeutically effective amount of flumazenil is betweenabout 1.5 and 2.5 mg/day.
 35. The method of claim 30 wherein thetherapeutic compound includes at least one of the following: fortifiedvitamin B complex, hydroxyzine, or gabapentin.
 36. The method of claim30 wherein the outpatient regimen includes at least one of diet,exercise, and cognitive therapy.
 37. The method of claim 30 wherein theselective chloride channel modulator is a partial allosteric modulatorat GABA_(A) receptor sites.
 38. The method of claim 37 wherein thepartial allosteric modulator acts with high potency but low efficacy atthe GABA_(A) receptor sites.
 39. The method of claim 37 wherein thepartial allosteric modulator acts to reset the GABA_(A) receptorreceptivity and increase chloride channel ion flow.
 40. The method ofclaim 30 wherein the selective chloride channel modulator acts to resetchanges in GABA_(A) subunits.
 41. The method of claim 30 wherein theselective chloride channel modulator is a partial agonist of theGABA_(A) receptor.
 42. The method of claim 30 wherein the selectivechloride channel modulator is at least one of a imidazobenzodiazepine ora derivative of ethyl8-fluoro-5,6-dihydro-5-methyl-6-oxo-4H-imidazo-[1,5-a][1,4]benzodiazepine-3-carboxylate.
 43. A method for treating alcohol abuse ina patient comprising the steps of: evaluating the patient; administeringa therapeutically effective amount of a composition comprisingflumazenil in a pharmaceutically acceptable carrier to the patientwherein the therapeutically effective amount of flumazenil is less than3 mg/day and is delivered in individual doses of 0.4 mg or less over aperiod of 20 minutes or less; monitoring the patient during treatment;prescribing the patient a therapeutic compound in addition to theflumazenil; and prescribing the patient an outpatient regimen.